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Physiol Rev
82: 187–204, 2002; 10.1152/physrev.00025.2001.
The Transporter Associated With Antigen Processing:
Function and Implications in Human Diseases
BRIGITTE LANKAT-BUTTGEREIT AND ROBERT TAMPÉ
Institut für Physiologische Chemie, Philipps-Universität Marburg, Marburg, Germany
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I. Introduction
A. Overview of antigen processing
II. Discovery, Genomic Organization, and Homology of the Transporter Associated With Antigen
Processing Genes
A. Cell lines with defects in MHC class I presentation
B. Characterization
C. Homologies
D. Genomic organization
E. Polymorphism
III. Regulation of the Transporter Associated With Antigen Processing Expression
A. Induction of TAP by IFN-␥ and other factors
B. Promoter of the TAP1 gene
IV. Structural Organization of the Transporter Associated With Antigen Processing Complex
A. A model for ABC transporters
B. The TAP complex
V. Substrate Specificity of the Transporter Associated With Antigen Processing
A. Peptides optimal for transport
B. Polymorphism and substrate specificity of TAP
VI. Transport Mechanism of the Transporter Associated With Antigen Processing
A. Binding of peptides
B. Translocation of peptides
C. Protein machinery for peptide recognition, transport, and loading of MHC class I molecules
VII. Human Diseases Associated With the Transporter Associated With Antigen Processing
A. Viral infections and virus persistence
B. Genetic diseases
C. Autoimmune disease and transplantation
D. TAP deficiency and tumor development
VIII. Concluding Remarks
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Lankat-Buttgereit, Brigittte, and Robert Tampé. The Transporter Associated With Antigen Processing:
Function and Implications in Human Diseases. Physiol Rev 82: 187–204, 2002; 10.1152/physrev.00025.2001.—The
adaptive immune systems have evolved to protect the organism against pathogens encountering the host.
Extracellular occurring viruses or bacteria are mainly bound by antibodies from the humoral branch of the
immune response, whereas infected or malignant cells are identified and eliminated by the cellular immune
system. To enable the recognition, proteins are cleaved into peptides in the cytosol and are presented on the
cell surface by class I molecules of the major histocompatibility complex (MHC). The transport of the antigenic
peptides into the lumen of the endoplasmic reticulum (ER) and loading onto the MHC class I molecules is an
essential process for the presentation to cytotoxic T lymphocytes. The delivery of these peptides is performed
by the transporter associated with antigen processing (TAP). TAP is a heterodimer of TAP1 and TAP2, each
subunit containing transmembrane domains and an ATP-binding motif. Sequence homology analysis revealed
that TAP belongs to the superfamily of ATP-binding cassette transporters. Loss of TAP function leads to a loss
of cell surface expression of MHC class I molecules. This may be a strategy for tumors and virus-infected cells
to escape immune surveillance. Structure and function of the TAP complex as well as the implications of loss
or downregulation of TAP is the topic of this review.
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0031-9333/02 $15.00 Copyright © 2002 the American Physiological Society
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BRIGITTE LANKAT-BUTTGEREIT AND ROBERT TAMPÉ
I. INTRODUCTION
A. Overview of Antigen Processing
FIG. 1. Overview of the antigen processing and presentation pathway via
major histocompatibility complex (MHC)
class I molecules. Endogenous proteins
are degraded by the proteasome. Cleavage products are transported into the lumen of the endoplasmic reticulum (ER)
by the transporter associated with antigen
processing (TAP) complex. Several molecules are involved in assembly and loading
of the MHC class I molecules, including
calnexin, calreticulin, tapasin, and ERp57
(for details, see Fig. 6). Stable MHC-peptide complexes leave the ER via the Golgi
compartment to the cell surface for recognition by cytotoxic T lymphocytes.
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The adaptive immune system has evolved to protect
the organism against pathogens. The recognition and
elimination of mutated or infected cells are performed by
the cellular immune system, which can be subdivided into
the class I major histocompatibility complex (MHC) and
the class II MHC pathways. MHC class I molecules are
present on the surface of nearly all nucleated cells,
whereas class II molecules are restricted to the cells of
the immune system. Here, we focus on antigen processing
via MHC class I molecules. The peptides needed for antigen presentation are generated in the cytosol by cleavage
of endogenous proteins and are displayed on the cell
surface by MHC class I molecules (Fig. 1). The chronic
presentation of self-protein-derived peptides does not
lead to a stimulation of T cells. During the development of
the thymus, the T cells with the ability to recognize the
self-peptides are deleted. In case of malignant transformation or viral infection of the cells, an additional set of
peptides is presented to the cytotoxic T lymphocytes
(CTL). The intracellular pathways leading to the generation of peptides, their binding to MHC molecules, and
presentation on the cell surface are called antigen pro-
cessing and presentation. The recognition of MHC class I
molecules as “self component” loaded with peptides from
“non-self” proteins by CTL leads to apoptosis or lysis of
malignant or infected cells. This is an essential process of
the cellular immune response (for review, see Refs. 116,
165). The pathway of antigen presentation by the MHC
class I complex is constitutively active in all nucleated
cells and is upregulated by inflammatory cytokines. Interference with this pathway has evolved as an effective
strategy for pathogens to evade immune response, leading
to chronic or latent infections. However, human patients
deficient in MHC class I antigen presentation do not appear to have a higher incidence of viral infections (33).
In the absence of infection, normal endogenous proteins are degraded in the cytosol, but MHC class I-associated peptides can be also derived from viral antigens in
the cytosol (159) as well as from proteins that are artificially introduced into the cytosol (104, 181). Inhibition of
protein breakdown in lysosomes did not affect MHC class
I presentation (106) and implied that the presented peptides were generated by proteases in an extralysosomal
pathway. The major mechanism for degrading proteins in
the cytosol is ATP dependent and highly conserved from
yeast to mammals (52). The resulting peptides are generated by a proteolytic particle, the 20S/26S proteasome (15,
28, 42, 182). The contribution of the 20S proteasome for
INTRACELLULAR PEPTIDE TRANSPORT IN ANTIGEN PROCESSING
Physiol Rev • VOL
encoded subunit ␤2-microglobulin and peptide (for review, see Refs. 91, 116). ␤2-Microglobulin makes extensive contacts with all three domains of the heavy chain
(21). For this reason, the conformation of the heavy chain
is dependent on the presence of ␤2-microglobulin. Allelic
polymorphism in the heavy chain primarily occurs at
residues involved in peptide binding and, therefore, alters
substrate specificity of the class I molecules (95, 96, 117).
In humans, there are three to six MHC class I alleles. This
small set of molecules has to bind the large pool of
peptides. Crystal structures of MHC class I molecules
provided further insight into this problem. How does a
single protein bind many different peptides? The antigenic peptide binds in a groove, which is formed by two
␣-helices on the rim and eight ␤-strands on the bottom of
the ␣1- and ␣2-domain of the heavy chain. The peptide is
fixed at the free COOH and NH2 terminus. Anchor residues at position two or three and at the COOH-terminal
residue pointing into the groove are also important for
binding. The groove accommodates peptides with eight or
nine residues in an extended conformation. The side
chains between most of these anchor residues point outside the groove. This binding motif explains the large pool
of peptides that is presented by one MHC class I allele.
Due to this arrangement, the variable region of the bound
peptide is monitored by the T-cell receptor (47, 48).
Efficient binding of peptides to the MHC class I molecules requires a macromolecular loading complex; the
assembly of this complex takes place in the ER and is
dependent on different chaperones that ensure correct
folding. After cotranslational translocation, the MHC
␣-chain associates with calnexin, a transmembrane calcium-dependent lectin with chaperone activity, followed
by formation of a noncovalent dimer with ␤2-microglobulin (for review, see Ref. 116). Calnexin is then replaced by
calreticulin, another calcium-dependent lectin, and
ERp57, a thiol reductase, is added to the complex, but the
exact time point of the interaction is unclear. Class I
heterodimers, associated with calreticulin and ERp57,
form the macromolecular loading complex with tapasin
and TAP. The glycoprotein tapasin is required for efficient
interaction of TAP and class I molecules (135). Meanwhile, there is evidence that calnexin and ERp57 bind to
the TAP-tapasin complex, generating an intermediate
which is capable of binding to the MHC class I-␤2-microglobulin dimers (37). The formation of this macromolecular complex is accompanied by the loss of calnexin and
binding of calreticulin. Furthermore, it could be demonstrated that the association of ERp57 to the complex is
tapasin dependent and in concordance with calreticulin,
not with calnexin (55). Despite the physical association of
TAP and the MHC class I molecules, it was shown by
inhibition of binding after antipeptide antibody application that possibly most TAP-transported peptides diffuse
through the lumen of the ER before being loaded onto
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the generation of antigenic peptides is further strengthened by the observation that proteasomal subunits, LMP2
and LMP7 (low-molecular-mass polypeptides), are encoded within the MHC locus (22, 51, 97). The catalytic
core of the proteasome is a 20S (700 kDa) cylindrical
particle composed of 28 subunits arranged in four heptameric rings. The outer rings are made up of seven
␣-subunits; the inner rings are composed of seven ␤-subunits. Whereas the ␣-subunits are thought to be primarily
responsible for structural and regulatory functions, the
␤-subunits harbor the catalytic centers (40, 93, 142). Another form of the proteasome is the 26S (1,500 kDa)
particle. It contains the 20S complex and additional subunits associated with regulation of its activity (118, 126).
The proteasome produces peptides with a size distribution of 3–30 residues with an optimum of 6 –11 residues
(39, 77). This size corresponds in part to the size of
antigenic peptides bound to MHC class I molecules. During interferon (IFN)-␥ stimulation, the three active proteasomal ␤-subunits are replaced by ␤i-subunits (131) to
build up a so-called “immunoproteasome.” Immunoproteasomes show a different cleavage pattern compared
with the proteasomes, thereby generating more peptides
with hydrophobic and basic COOH termini (131); both of
them are favored for uptake by transporters associated
with antigen processing (TAP) into the endoplasmic reticulum (ER) and for optimal binding to MHC class I
molecules. About one-third of newly synthesized proteins
are rapidly degraded by proteasomes under physiological
conditions (139, 162). However, peptides are also generated, at least in part, by other proteases, such as the
IFN-␥-inducible leucine aminopeptidase (19) or a giant
cytosolic protease system, the tripeptidyl peptidase II (49,
50). It has been shown that blocking proteasomal activity
does not inhibit the presentation of antigenic peptides
derived from influenza viral proteins (173). Meanwhile,
there are results that breakdown of ovalbumin by the
proteasome primarily produced peptide variants with
NH2-terminal extensions compared with the immunodominant peptide, suggesting that MHC class I-bound peptides
are NH2-terminally trimmed by cytosolic aminopeptidases
(23). In addition, proteolytic trimming in the ER may also
produce epitopes after transport (132).
The TAP translocates peptides generated by the proteasome complex from the cytosol into the lumen of the
ER. In the ER, peptides are loaded onto the newly synthesized MHC class I molecules. Deletion or mutation of
TAP severely affects the translocation of peptides into the
ER. Because binding of peptides stabilizes the MHC complex and induces subsequent export to the cell surface for
presentation to T-cell receptors (Fig. 1), any defect, which
impairs the transport of peptides, results in reduced surface expression of MHC class I molecules. MHC class I
heterotrimers consist of a MHC encoded polymorphic
␣-chain (heavy chain) as well as the invariant non-MHC
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BRIGITTE LANKAT-BUTTGEREIT AND ROBERT TAMPÉ
cell lines were unable to present intracellular antigens on
the cell surface. It soon became clear that this defect was
due to deletions in the region of the MHC locus and most
likely involved a gene or genes that were responsible for
delivering peptides to the lumen of the ER and/or loading
of these peptides onto newly synthesized class I molecules. These genes were tentatively mapped to the MHC
locus by analysis of gene deletions in one of these mutant
cells (24). In the following, four groups independently
described candidate genes from the MHC region for a
factor that would transport peptides across the ER membrane (36, 103, 148, 160). In 1991, a World Health Organization (WHO) nomenclature committee for factors in the
HLA system renamed these genes to TAP (155). RING4,
PSF1, mtp1, and HAM1 are now TAP1, and RING11, PSF2,
mtp2, and HAM2 are renamed TAP2.
II. DISCOVERY, GENOMIC ORGANIZATION,
AND HOMOLOGY OF THE TRANSPORTER
ASSOCIATED WITH ANTIGEN
PROCESSING GENES
B. Characterization
A. Cell Lines With Defects in MHC Class I
Presentation
Peptides produced in the cytosol must pass into the
lumen of the ER before they can bind to MHC class I
molecules. The first indication that this translocation into
the ER requires a transporter was based on studies dealing with various cell lines with a strongly reduced level of
MHC class I molecules on the cell surface (91, 158). These
mutant cell lines exhibit a low cell-surface expression of
MHC class I and are deficient in antigen presentation.
Although the expression levels of MHC class I heavy chain
and ␤2-microglobulin are normal and peptides exogenously added or introduced into the ER by signal sequences were efficiently presented (8), these defective
The genes for human TAP1 and TAP2 are located in
the MHC II locus of chromosome 6 and comprise 8 –12 kb
each (Fig. 2) (161). Deletions of either or both of the TAP
genes result in greatly reduced surface expression of
MHC class I molecules (24, 65, 158). These defects can be
partly corrected by addition of exogenously supplied
class I-binding peptides (157). The functional impact of
TAP1 and TAP2 was proven by transfection of defective
cell lines with TAP2 and/or TAP1 genes, restoring antigenpresenting activity (12, 124, 149, 150). These observations
implicated that MHC class I molecules are unstable under
physiological conditions in the absence of appropriately
bound peptides and that the majority of binding peptides
are provided by a TAP-mediated transport. Moreover,
TAP1-deficient mice created by gene targeting exhibit a
phenotype consistent with that observed in TAP-defective
cell lines. These mice show a severely reduced class I cell
surface expression and fail to present cytosolic antigens
to cytotoxic T cells (171).
FIG. 2. The location of the TAP genes in the
human MHC class II complex (HLA) in a schematic representation. The scale is intended as a
rough guide only. Boxes indicate the approximate position of the genes. The figure underneath the schematic location of the genes illustrates the participation of the gene products in
peptide generation and transport.
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MHC class I molecules (63). The binding of peptides to
class I heterodimers releases the loaded MHC class I
molecules from the assembly complex for transport to the
cell surface via the Golgi apparatus and the trans-Golgi
network. The export from the ER by ER-budding vesicles
is the rate-limiting step, and the multitude of ER-to-Golgi
transport is independent of peptide loading or dissociation from TAP (151).
During the last years, the comprehension of structure
and functions of TAP increased significantly, stressing the
importance of this transporter for the adaptive immune
response. A growing number of studies deal with the
implications of disturbed TAP function in various human
diseases from viral infections to tumor development. In
this review, the current knowledge about TAP and its
implications for diseases are summarized.
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191
E. Polymorphism
The sequences of the TAP1 and TAP2 coding regions
were determined, and alignment of TAP1 and TAP2
showed the highest homology in a stretch of 200 amino
acids near the COOH terminus. This region contains three
characteristic motifs. The Walker A (P loop) and Walker B
motifs form a highly conserved ATP-binding cassette
(ABC). ATP and other nucleotides bind to these sites and
are hydrolyzed in a Mg2⫹-dependent manner (107, 134,
177). A so-called C loop, which consists of six to eight
conserved amino acids, is located in between the Walker
A and B motif. There is genetic evidence that generally a
so-called “EAA” sequence found in the last cytosolic loop
of the membrane-spanning domain of bacterial ABC
transporters interacts with the C loop, thereby coupling
ATP hydrolysis to the transmembrane spanning domain
(27, 32). Due to the sequence homology, TAP1 and TAP2
belong to the superfamily of ABC transporters and, in
more detail, to subfamily B. A conserved nucleotide-binding domain (NBD) and a transmembrane domain (TMD)
of about six membrane-spanning segments characterize
this protein family. A functional unit comprises two NBDs
and two TMDs. ABC transporters are found in all domains
of life throughout the animal and plant kingdoms, bacteria, and archea (61). They form the largest and most
diverse family of membrane-spanning transport proteins.
TAP1 and TAP2 are polymorphic in all species examined, and there is clear evidence that this polymorphism can
affect the substrate specificity of the transporter (56, 101,
121, 122, 180). On the other hand, a functional polymorphism was only demonstrated for rat TAP (112) and for the
human TAP2iso splice variant (180). The rat TAP from the
RT1u strain as well as human TAPiso most efficiently translocates peptides with hydrophobic COOH-terminal residues,
while TAP from the rat RT1a strain is permissive for peptides
containing hydrophobic and basic COOH termini (56, 101).
Human TAP apparently resembles more closely rat TAP
from the RT1a strain with a broader specificity, whereas
mouse TAP has a higher similarity to rat TAP from the RT1u
strain. The level of structural polymorphism in human and
mouse TAP (an average of 2–5 amino acid substitutions
between alleles) (26, 123) is reduced compared with that
seen in rat (25 positions of allelic variations in the rat TAP2
gene) (121, 125).
Nonetheless, the TAP genes are polymorphic both in
mice and humans. Several alleles of human TAP1 and TAP2
have been identified in different populations (133). This
suggests that functional differences between alleles exist,
even though initial attempts to demonstrate such functional
polymorphism have been unsuccessful (31, 114, 141, 168).
On the other hand, data concerning polymorphism of the
TAP genes in different human populations point to little, if
any, functional significance (69, 75, 99, 133).
D. Genomic Organization
The genomic structures of the human and mouse
TAP genes have been established (17, 160). As mentioned
in section IIB, the human TAP1 and TAP2 genes are located in the MHC II locus of chromosome 6 and are 8 –12
kb in size. They consist of 11 exons (54); 8 of them are of
the same length, although the intron sizes vary significantly. The remaining three exons 1, 9, and 11 differ in
length by 100, 3, and 78 nucleotides, respectively. All 11
intron/exon boundaries are identical in their classes and
follow the GT/AG rule. Sequence comparisons from human to salmon TAP1 showed the expected phylogenetic
differences (for example, 98.8% homology of human with
gorilla TAP1, 69.2% with hamster, and 40% with salmon).
The analysis indicates that the degree of relatedness between human TAPs is similar to that between each gene
and its homologs in rodents (66). The homology between
TAP1 and TAP2 in all species examined up to now is
⬃35%, although they share a similar predicted membrane
topology. Therefore, it is speculated that the genes have
evolved from a common ancestral gene by duplication
before the development of the adaptive immune system in
vertebrates (16).
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III. REGULATION OF THE TRANSPORTER
ASSOCIATED WITH ANTIGEN
PROCESSING EXPRESSION
A. Induction of TAP by IFN-␥ and Other Factors
MHC class I molecules are expressed at low levels in
most cells and are strongly induced by cytokines such as
IFN-␥ (for a review, see Ref. 42). Increased expression of
MHC class I molecules correlates with increased CTL function. Therefore, it was of special interest to study the regulation of TAP gene expression. Both TAP1 and TAP2 mRNAs
are upregulated ⬃10- to 20-fold within 12 h by IFN-␥,
whereas HLA class I heavy chain mRNA is induced more
slowly, increasing only 10-fold in 24 h (13, 94). Although
TAP1 and TAP2 proteins are also rapidly induced, HLA class
I heavy chains and surface expression increase more slowly,
accompanied by an increased peptide transport capacity.
Comparable to these data, gene transfer of a cDNA encoding
IFN-␥ into a human renal carcinoma cell line results in a high
constitutive expression of TAP, but allospecific CTL reaction was not better stimulated with IFN-␥ transductants than
with unmodified tumor cells (138). In some cases, TNF-␣
can lead to an increase in TAP1 levels by in vitro treatment
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C. Homologies
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BRIGITTE LANKAT-BUTTGEREIT AND ROBERT TAMPÉ
belong to the superfamily of ABC transporters, comprising a large number of polytopic membrane proteins. Members of this family transport a diverse set of molecules
ranging from ions to large proteins across cell membranes
in an ATP-dependent manner (for review, see Refs. 38,
61). ABC transporters play an important role in different
(patho)physiological processes, such as cystic fibrosis
(cystic fibrosis transmembrane conductance regulator),
multidrug resistance (e.g., MDR1 or MRP1), high-density
lipoprotein deficiency (Tangier disease, ABCA1), retinitis
pigmentosa 19 and age-related macular degeneration
(ABCR), hyperinsulinemic hypoglycemia of infancy
(SUR1), and adrenoleukodystrophy (ALD) (for review,
see Ref. 79). As mentioned in section II, all ABC transporters share two conserved cytoplasmic ATP-binding domains and two hydrophobic domains, consisting of 5–10
transmembrane stretches. These stretches are composed
of ␣-helices, lining up the putative translocation pore. One
to four genes can encode all four domains.
B. Promoter of the TAP1 Gene
B. The TAP Complex
The human TAP genes contain no TATA box motifs
in the 5⬘-flanking sequences but putative GC-rich elements (Sp1 binding sites, 128 nucleotides upstream of the
translation start codon for TAP1 and 79 nucleotides upstream in the case of TAP2) (17). Site-directed mutagenesis of the Sp1 binding site leads to a threefold reduction
of basal promoter activity of the TAP1 gene (179). The
promoter is induced by several IFN-␥-responsive elements and a p53-responsive element, which act independently from each other (185). However, the activity of the
p53-responsive element was proven in vivo only in context with a heterologous minimal promoter, and no data
are available concerning the significance of this element
in the homologous promoter region. It should be noted
that the TAP1 gene is coordinately regulated by a bidirectional promoter of 593 bp, also directing the divergently
transcribed gene of LMP2, the ␤-type proteasomal subunit
␤1i. Both genes are induced by tumor necrosis factor
(TNF)-␣ via a NF-␬B-like enhancer (68). The cytokinestimulated expression of TAP1 and LMP2 concordantly
with class I genes suggests a mechanism linking transporter levels with class I production.
Immunoelectron and immunofluorescence microscopy analyses have localized TAP1 and TAP2 in the ER
and the cis-Golgi (78, 98), retarded by a so far uncharacterized ER retention signal. This subcellular distribution
is consistent with the location where MHC molecules bind
peptides. The homology with other ABC transporters
points to a functional TAP protein either as a homodimer
of TAP1 or TAP2 or a heterodimer. Indeed, immunoprecipitations with antisera directed against TAP1 coprecipitated TAP1 and TAP2 (76). Comparisons of the phenotypes of different mutant cell lines suggest, and
heterologous coexpression of TAP1 and TAP2 in insect
cells and yeast demonstrate, that neither TAP1 nor TAP2
forms a functional homodimer (98, 166). Furthermore, no
additional factors of the immune system are required for
TAP function. TAP1 and TAP2 are found to be nonglycosylated, although TAP1 has three putative glycosylation
sites; however, two are facing the cytosol, and one is
placed in an ER loop too short for effective glycosylation
(98).
Hydrophobicity analysis and sequence alignments of
TAP proteins with related ABC transporters point to a
two ⫻ six transmembrane helix model of TAP, extended
by additional four and three transmembrane helices predicted for the highly diverse NH2-terminal domain (Fig. 3)
(152). Up to now, the function of these NH2-terminal
hydrophobic extensions is unclear. As also found for
other ABC transporters located in the ER, both TAP molecules lack a known NH2-terminal signal sequence for the
import into the ER, indicating that an internal signal
sequence may exist. Experiments with truncated proteins
suggest that TAP1 and TAP2 contain multiple ER reten-
IV. STRUCTURAL ORGANIZATION OF THE
TRANSPORTER ASSOCIATED WITH
ANTIGEN PROCESSING COMPLEX
A. A Model for ABC Transporters
As mentioned before, human TAP1 (748 amino acids)
and human TAP2 (686 amino acids, 653 for TAP2iso)
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of tumor samples (109). Another cytokine, interleukin-10,
expressed in a murine tumor cell line, has an opposite effect;
a reduction of TAP level was observed (136).
Tumor cells may evade tumor surveillance by acquiring mutations that inhibit antigen processing via MHC
class I. Because more than 50% of human tumors have a
dysfunctional p53, this mutation may diminish or abrogate the host tumor surveillance. Therefore, the effect of
p53 on TAP1 expression was investigated (185). The authors observed that p53 as well as DNA-damaging agents
could increase TAP1 levels and subsequent MHC class I
cell surface expression, indicating that a dysfunctional
p53 in human tumor cells would not induce TAP1 after
genotoxic stress. These results suggest that tumor surveillance may be a mechanism by which p53 acts as a tumor
suppressor. Furthermore, several breast cancer cell lines
showed lower expression levels of TAP mRNA compared
with normal breast epithelial cells and a cell cycle-dependent regulation (6).
INTRACELLULAR PEPTIDE TRANSPORT IN ANTIGEN PROCESSING
193
FIG. 3. Membrane topology of the human TAP complex. The transmembrane helices are predicted from hydrophobicity plots and sequence alignments with other
ABC transporters. The unique NH2-terminal domains (N)
of TAP1 and TAP2 are very hydrophobic, comprising four
and three predicted transmembrane helices, respectively
(orange cylinders). Numbers in the cylinders indicate the
amino acid residues beginning and ending the transmembrane domains. The nucleotide binding domain consists of
the Walker A and B motifs (A, B) and the so-called C loop
(C), possibly interacting with membrane-spanning domains, in particular with the EAA-like motif (E). The orange lines illustrate binding regions for peptides as identified by photo-cross-linking experiments (113).
Physiol Rev • VOL
transporter P-glycoprotein (92). Because of the discrepancies in the models, further studies are needed to clarify
the structural organization and membrane topology of
TAP.
V. SUBSTRATE SPECIFICITY OF THE
TRANSPORTER ASSOCIATED WITH
ANTIGEN PROCESSING
A. Peptides Optimal for Transport
The characterization of antigenic epitopes is very
important for the knowledge about the immunologic response and the development of vaccination strategies.
Therefore, the substrate specificity of TAP is well studied.
The first results were obtained by trapping transported
peptides in the ER via glycosylation (110). The comparison of glycosylated peptides differing in length or amino
acid composition provided information about length and
sequence preferences of the transported peptides (for
review, see Refs. 10, 165). Peptides with a length of 8 –16
amino acids bind to TAP with equal affinity (170); translocation into the ER was most efficient for peptides of
8 –12 amino acids (83). Transport of peptides with even 40
amino acids was observed, but with lower efficiency.
Therefore, TAP transports preferentially peptides with a
similar or slightly larger size suitable for MHC class I
binding. Another approach to study TAP selectivity was
realized determining the equilibrium binding affinity constant (164, 170). Equal binding affinities were found for
peptides ranging from 8 to 16 amino acids (170). The only
discrepancies exist in the absolute values between binding affinity and transport efficiency (10, 164, 169). The
glycosylation method includes several side reactions such
as peptide transport, glycosylation, degradation, and export and, therefore, does not necessarily reflect transport
rates. Thus the binding assay seems to be more accurate
for the analysis of substrate specificity.
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tion signals in the transmembrane regions, including the
first transmembrane segment (176). The hydrophobic
transmembrane regions are linked to the nucleotide binding domains, which contain the conserved Walker A and B
motifs for ATP-binding and hydrolysis and, based on this
model, are located in the cytosol. According to this model,
the complex is highly asymmetric with respect to the
cytosolic and ER-luminal regions; large cytosolic loops
and both NBDs are located in the cytosol, but only a small
portion (⬍10%) reaches toward the ER lumen (152). It
was further proposed that the pore-forming domains of
the TAP1 and TAP2 heterodimer are aligned in a headhead/tail-tail orientation (175), which however contradicts the TMD organization of P-glycoprotein (92).
Peptides are photo-cross-linked to TAP1 and TAP2,
suggesting that both subunits are involved in peptide
binding (10, 11). More recently, the peptide-binding region
was mapped after peptide photo-cross-linking, digestion
of TAP by trypsin and/or bromocyan, and subsequent
immunoprecipitation with antibodies directed against different epitopes of TAP (113). This analysis revealed a
similar binding region for TAP1 and TAP2, comprising the
cytosolic loops between TM4 and TM5 and a COOHterminal stretch of ⬃15 amino acids after TM6 (Fig. 3).
Deletion of some of these potential peptide-binding sites
between residues 366 and 405 of TAP1 resulted in defective peptide transport (130). Due to the topological model
of TAP (1, 152), all these regions are expected to be
exposed to the cytosol. Recently, a slightly different
model of the TAP complex was presented (176). With a
set of COOH-terminal deletions for the TAP1 and TAP2
subunits, the topology of TAP was investigated. Eight and
seven transmembrane segments were identified for TAP1
and TAP2, respectively. Due to this model, no evidence
for membrane integration was obtained for the two hydrophobic regions adjacent to the nucleotide binding domains for both subunits. However, this model is in contrast to the established membrane topology of the ABC
194
BRIGITTE LANKAT-BUTTGEREIT AND ROBERT TAMPÉ
The contribution of each peptide residue to the affinity for TAP was determined systemically by screening
combinatorial peptide libraries (163) (Fig. 4). With this
method, the average affinity of a randomized peptide
mixture with one defined residue is compared with a
totally randomized peptide library. Therefore, the influence of each peptide residue was analyzed independent of
a given sequence context on the affinity of TAP. The effect
of each amino acid residue on the stabilization of peptide
binding to TAP was determined. The strongest differences
were observed for the COOH-terminal amino acid and the
first three NH2-terminal residues. The amino acids in be-
tween do not significantly contribute to substrate specificity of TAP but are necessary for recognition of a MHC
class I-bound peptide by the T-cell receptor. This binding
motif combines two advantages: 1) maximal diversity of
residues 5– 8 in the antigenic peptide where T-cell receptor recognition and no selection by TAP occurs, and 2)
maximal binding affinity at the termini for TAP. The
matched preferences of human TAP and MHC class I
suggest a coevolution of the genes (165) as it was also
proposed for rat TAP and MHC class I molecules (72).
B. Polymorphism and Substrate Specificity of TAP
4. Peptide specificity for the TAP transporter as determined by
combinatorial peptide libraries (164). Top panel: substrate specificity for
TAP. The first three NH2-terminal amino acids and the last COOHterminal amino acid contribute significantly to the stabilization of peptide binding to TAP. Middle panel: favored amino acids at the individual
positions with negative ⌬⌬G values (favored residues) are shown in
blue, and positive ⌬⌬G values (disfavored residues) are in red. For
example, for the first position the amino acids K, N, and R are favored,
and D, E, and F are disfavored. Bottom panel: a model of the substratebinding pocket of TAP.
FIG.
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VI. TRANSPORT MECHANISM OF THE
TRANSPORTER ASSOCIATED WITH
ANTIGEN PROCESSING
A. Binding of Peptides
Peptide transport by TAP is a multistep process
(170). The peptide-binding pocket is formed by TAP1 and
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The strongest differences in peptide binding affinity
to TAP were detected at the COOH terminus of peptides
(101, 103, 141, 163). As mentioned in section II, a limited
degree of sequence polymorphism has been found for
human and mouse TAP genes by restriction length polymorphism and sequence analysis, but no measurable alteration in function of these gene products was observed
(133, 141). However, it has been shown that in rats, TAP
polymorphism has an influence on peptide selectivity.
TAP from the rat strain RT1a as well as human TAP
translocates peptides with a broad specificity (hydrophobic or basic amino acids at the COOH terminus), whereas
TAP from the rat strain RT1u and mouse TAP prefers
peptides with hydrophobic COOH termini. This pattern
correlates with the predominant peptide binding profiles
of human and mouse MHC class I molecules.
Although human TAP genes are less allelically diverse than rat genes, another possibility to generate different substrate specificity in the human transporter was
recently reported (180). An alternative splicing variant of
the human TAP2 gene was described termed TAP2iso. It
lacks exon 11, a part of the coding region and the original
3⬘-untranslated region, but contains the newly identified
exon 12. TAP2iso mRNA was normally coexpressed with
TAP2 mRNA in all human lymphocyte cell lines examined.
TAP1-TAP2iso transporters exhibited distinct and opposing influences on peptide selectivity, more resembling the
TAP complex from rat strain RTu and mouse TAP. The
common expression of an alternative splice product of
the TAP2 gene may contribute to a broadened immune
diversity.
INTRACELLULAR PEPTIDE TRANSPORT IN ANTIGEN PROCESSING
195
B. Translocation of Peptides
The translocation strictly requires hydrolysis of ATP,
because nonhydrolyzable ATP analogs do not promote
peptide transport. In addition to ATP, UTP, CTP, and GTP
(9) can energize peptide translocation. Direct binding of
nucleotides was demonstrated by 8-azido-ATP photocross-linking experiments (107, 134, 176). ATP and ADP
have similar affinities for TAP; therefore, ADP and other
nucleoside diphosphates competing for ATP binding inhibit peptide translocation. The ATPase activity of TAP is
substrate specific and tightly coupled to peptide binding,
indicating that peptide binding is a prerequisite for ATP
hydrolysis, thereby possibly preventing waste of ATP
without transport of peptides (53). ATP hydrolysis follows Michaelis-Menten kinetics with a turnover number
kcat of ⬃5 ATP/s. This turnover rate is sufficient to account for the essential role of TAP in the overall process
of antigen processing. Interestingly, sterically restricted
peptides that bind to but that are not transported by TAP
do not stimulate the ATPase activity of TAP (53). Both
nucleotide-binding domains of TAP interact with ATP,
even if expressed separately (107, 176). A structural rearrangement of the NBDs by peptide binding seems to
function as a molecular switch to activate the ATPase of
TAP, since the NBDs alone are unable to hydrolyze ATP
(107, 177). It is known that both NBDs are essential for
TAP function, since mutation of one NBD leads to a loss
of transport action (25). It may be that hydrolysis at one
NBD starts the peptide transport, whereas hydrolysis at
the second NBD is necessary for completion of the translocation cycle and perhaps for the reconversion of the
initial substrate-binding site. A model of the peptide translocation by the TAP complex is presented in Figure 5.
Lysine mutation of the Walker A motif of TAP1 and TAP2
points to distinct functional properties of both NBDs (84,
Physiol Rev • VOL
FIG. 5. Current model of peptide binding and transport by the TAP
complex. ATP and/or ADP as well as peptide bind independently to TAP
in the cytosol. Peptides are shown as blue triangles. It is unknown if
both nucleotide binding domains are loaded with ATP at the beginning
of the cycle. Peptide binding induces a conformational change of the
TAP complex. This structural reorganization may trigger the ATP hydrolysis and translocation of the peptide.
137). Even if the data concerning nucleotide and peptide
binding after mutation of human TAP1 or TAP2 are somehow contradictory, it seems that ATP binding to both subunits is tightly regulated and transport cycle dependent.
Results with glycine mutations in the Walker A motif of rat
TAP1 or TAP2 indicate that binding of ATP to TAP1 is the
first step in energizing the transport cycle and induces ATP
binding to TAP2 (4). Future investigations are needed to
clarify these conflicting observations.
TAP only transports peptides longer than 7 residues;
the efficiency drops off with peptides longer than 12
amino acids, but there is no clear limit (9, 22, 101, 145). A
complicating factor for analyzing TAP-dependent transport is the presence of an efficient ATP-dependent peptide
export system out of the ER and into the cytoplasm (82,
132, 140). Peptides with low affinities may not be rapidly
bound to the MHC class I molecules and are therefore
available for export; this may be another mechanism to
select for high-affinity peptides binding to the MHC class
I molecules.
C. Protein Machinery for Peptide Recognition,
Transport, and Loading of MHC Class I
Molecules
The view that TAP plays an important role in class I
assembly derives from the observation that it not only
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TAP2. Peptides associate with TAP in an ATP-independent manner at low temperatures (164). So far, no indication for a second binding site was found by direct
peptide binding or competition assays as well as by photocross-linking experiments. With the use of fluorescencelabeled peptides, the association pathway to TAP could
be kinetically dissected in real time (112). In a fast bimolecular association step, peptide binds to TAP, followed
by a slow isomerization of the TAP complex. It is suggested that this structural reorganization of the molecule
triggers ATP hydrolysis and peptide translocation across
the membrane. The binding step determines the selectivity of TAP (112). The conformational change of TAP also
influences its lateral mobility, shown by tagging the TAP1
subunit with green fluorescent protein (127). The mobility
of the TAP complex increases when it is inactive and
decreases during peptide translocation.
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BRIGITTE LANKAT-BUTTGEREIT AND ROBERT TAMPÉ
Peptide binding to MHC class I molecules is a prerequisite for dissociation of TAP-MHC complexes. This
peptide-mediated detachment depends on conformational
signals from the TAP complex induced by ATP binding
(80). Recent data suggest that release of peptide-loaded
MHC class I molecules is predominantly dependent on the
conformation of TAP1 (4). Therefore, the dynamic activity of the TAP-MHC class I complex is synchronized with
the peptide binding and translocation cycle of TAP.
VII. HUMAN DISEASES ASSOCIATED WITH
THE TRANSPORTER ASSOCIATED WITH
ANTIGEN PROCESSING
A. Viral Infections and Virus Persistence
CTL recognize and eliminate virus-infected cells. This
requires the presentation of viral peptide fragments by
MHC class I molecules at the cell surface. Persistent
viruses, such as the large DNA-containing herpes viruses,
have been forced to evolve different strategies to evade
the immune defense, which means especially by interfering with antigen processing and presentation (for review,
see Refs. 59, 120).
The immediate early protein ICP47 encoded by herpes simplex virus type 1 (HSV-1) was identified to be
responsible for the downregulation of the MHC class I
surface expression in human fibroblasts (183). Therefore,
HSV-infected cells are masked for immune recognition by
CTL. ICP47 inhibits the TAP-mediated peptide transport
into the ER by binding to the TAP complex (41, 62). It was
demonstrated that ICP47 binds with high affinity at least
in part to the peptide-binding site of TAP, thereby blocking the first and essential step in the translocation pathway (3, 156). Recently, a similar downregulation of peptide transport activity was observed in bovine epithelial
cells infected with bovine herpesvirus-1 (64). The interaction of human ICP47 and the TAP complex is species
specific, since ICP47 has a 100-fold higher affinity for
human than for murine TAP (3, 156). Meanwhile, the
critical amino acids of ICP47, which are necessary to
inhibit TAP function, have been identified (111, 159).
These amino acids comprise the NH2-terminal region
FIG. 6. The macromolecular transport and chaperone
complex. The de novo-synthesized MHC-encoded heavy
chains (left) assemble with calnexin and ␤2-microglobulin.
After binding to ERp57 and calreticulin, the MHC class I
molecules can associate via tapasin to the TAP complex.
Peptides are translocated into the lumen of the ER by TAP
and loaded onto the MHC class I complex, which leaves
the ER to the cell surface.
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delivers peptides to the ER, but also is involved in the
formation of a large loading complex critical for class I
maturation (Fig. 6). A number of other proteins are required for the assembly and loading of MHC class I molecules, and several chaperone-like proteins have been
identified (for review, see Refs. 29, 87). At least four
proteins, calnexin, calreticulin, ERp57, and tapasin, are
involved in the assembly of heavy chain and ␤2-microglobulin. The dominant chaperones associated with newly
synthesized class I heavy chains are calnexin and calreticulin (67, 135). Calreticulin is a soluble homolog to calnexin and shares its specificity for monoglycosylated Nlinked glycans. The mechanism how calnexin/calreticulin
facilitates folding is not understood, but it is suggested to
be involved in a binding and release cycle. If the association of these chaperones is disturbed by glucosidase
inhibitors, the folding and subsequent surface expression
of MHC class I molecules are dramatically reduced (153,
172). An additional housekeeping molecule, called ERp57,
is part of the large multisubunit TAP-tapasin-MHC complex (67, 90, 105). ERp57 is a member of the thioredoxin
family of enzymes and also binds to the complex in a very
early step of the maturation, probably supporting the
correct formation of disulfide bridges.
The MHC class I molecules interact with the TAP
complex via an ER-resident type I glycoprotein, named
tapasin for TAP-associated glycoprotein (88, 115). Tapasin is a transmembrane protein that, like MHC molecules,
is a member of the immunoglobulin superfamily. It has an
apparent molecular mass of 48 kDa. Tapasin mediates
complex formation and the cross-talk of structural information of MHC and TAP and is therefore important for
class I assembly and editing (135). In its absence, the
assembly in the ER is impaired, and MHC class I surface
expression is reduced. Tapasin has two independent functions: 1) it increases the level of TAP, thereby increasing
the efficiency of peptide transport, and 2) it associates
with MHC class I molecules, thereby facilitating directly
loading and assembly of class I molecules (14, 86). Approximately four MHC class I molecules seem to be linked
via four tapasin to one TAP complex (115). Truncated
tapasin missing the transmembrane region and the cytosolic tail appears to be not associated with TAP, but still
rescues MHC class I expression (86).
INTRACELLULAR PEPTIDE TRANSPORT IN ANTIGEN PROCESSING
Physiol Rev • VOL
disease recurrence. These findings suggest that HPV may
evade immune recognition by downregulating MHC class
I cell surface expression via decreased TAP1 levels. The
expression of TAP1 could be used for prognostic evaluation of disease severity. Moreover, a similar mechanism
with decreased TAP1 and MHC class I protein was described in other malignancies induced by HPV, for example, HPV-16- and HPV-18-infected carcinomas of the cervix (30). Similar to HPV, the Epstein-Bar virus (EBV) has
evolved a strategy to avoid immune surveillance by downregulation of TAP1 (184). EBV expresses a protein, vIL-10,
that is similar in sequence to human interleukin-10. vIL-10
downregulates the expression of the TAP1 gene, but not
of the TAP2 gene, thereby affecting the transport of peptides into the ER. This mechanism might contribute to the
persistence of EBV-infected cells in the human host.
B. Genetic Diseases
There is little knowledge about human genetic TAP
defects. Bare lymphocyte syndrome (BLS) is known to be
characterized by a severe downregulation or deficiency of
MHC class I and/or MHC class II molecules. In type 1 BLS,
the defects are assigned to the MHC class I, whereas in
type 2, the MHC class II molecules are affected. The
characterization of 22 patients with type 1 BLS revealed
the existence of 3 clinically and immunologically distinct
subsets (for review, see Ref. 45). Two groups include
patients with a defective transcription of MHC class I
molecules and ␤2-microglobulin. The third group is the
best-characterized subset of type 1 BLS and comprises 15
patients from different families. The reduced MHC class I
cell surface expression manifests with necrotizing granulomatous skin lesions and recurrent bacterial infections.
Tissue typing of 10 patients indicated that a defect TAP
complex is responsible for the downregulation of MHC
class I molecules. Studies of two families revealed that
the disease is caused by deficiency of TAP2, which is
mainly due to a premature stop codon resulting in a
nonfunctional TAP complex (33, 154). The homozygous
TAP2 ⫺/⫺ siblings of one family have reduced expression
of MHC class I molecules on the cell surface and reduced
amounts of CTL. On the other hand, these people do not
show an increased susceptibility to viral infections. A
fraction of antigenic peptides seems to be transported
into the ER lumen in a TAP-independent manner, although TAP appears to be the dominant pathway under
normal conditions (34).
Five adults with a syndrome resembling Wegener’s
granulomatosis were also found to exhibit low surface
expression of MHC class I molecules and defective expression of the TAP complex (100). In two patients, a
mutation in the TAP2 gene was identified, responsible for
this defective expression of the TAP complex.
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from residue 3 to 34 (111). This active domain of ICP47
appears to be mainly unstructured in aqueous solution
(18). In the presence of lipidlike environment, an ␣-helical
structure is induced, which is composed of two helical
regions extending from residues 4 –15 and 22–32 connected by a flexible loop (18, 119). On the basis of these
results, therapeutic drugs could be designed that are potent immune suppressors or that are applicable in novel
vaccination strategies against HSV, restoring the ability of
the immune system to recognize the infected cells.
Human cytomegalovirus (HCMV) encodes at least
four proteins that decrease the cell surface expression of
MHC class I molecules (for review, see Ref. 59). An ERresident glycoprotein, called gpUS6, inhibits the TAPmediated peptide transport. The mechanism is probably
due to binding of gpUS6 to the ER-luminal part of the TAP
complex (2, 58, 85). Peptide binding is not affected by
gpUS6; also, the association of tapasin, calreticulin, and
MHC class I molecules to TAP appears normal. Recent
findings indicate that gpUS6 binds to TAP and stabilizes a
TAP1 conformation, which is unable to bind ATP, and
subsequently, peptide translocation is inhibited (60).
Overexpression of TAP with IFN-␥ induction overrides
the inhibition of peptide transport by gpUS6, but there are
other proteins of HCMV, expressed in the early phase of
infection, which interfere in a different way with the MHC
class I pathway of antigen presentation (57; for a review,
see Ref. 178).
Another herpes virus that hampers the MHC class I
immune response is the porcine pseudorabies virus (PrV).
It causes a highly infectious disease of pigs and can exist
in a latent form in several tissues, but mainly in the
trigeminal ganglia. PrV infects epithelial cells of mucosal
surfaces and spreads by cell-to-cell contact. It could be
shown that inhibition of peptide transport activity of the
TAP complex is one of the mechanisms by which an early
PrV protein downregulates MHC class I expression (7).
Two viruses that do not belong to the herpes virus
family but interfere with the MHC class I pathway and
TAP function are the adenovirus and the human papilloma virus (HPV) (20, 167). Adenoviruses encode a protein, E3/19K, that directly binds MHC class I molecules,
trapping them in the ER (20). Moreover, E3/19K seems to
bind to TAP and inhibits the tapasin action, thereby preventing MHC class I/TAP association (20). HPV causes
recurrent papillomatosis that is characterized by a variable clinical course and that can include significant morbidity and occasional mortality. Complete eradication of
HPV is rare with repeated surgical excision. The knowledge about the mechanism responsible for the persistence of latent HPV would be valuable for treatment. In
laryngeal papilloma tissue biopsies and in cell culture of
primary explants, a downregulation of TAP1 was observed (167). More significantly, the amount of TAP1 protein expression correlated inversely with the frequency of
197
198
BRIGITTE LANKAT-BUTTGEREIT AND ROBERT TAMPÉ
C. Autoimmune Disease and Transplantation
The participation of TAP in autoimmune diseases is
discussed controversially. For several patients with diverse MHC-linked autoimmune diseases, such as type I
diabetes, Sjogren’s syndrome, Graves’ disease, and Hashimoto’ disease, a downregulation of mRNA levels for TAP1
and TAP2 was found in varying degrees (43). These data
suggest that defective transcription of TAP genes can
contribute to reduced MHC class I cell surface expression
in autoimmune diseases. Cells lacking MHC class I molecules might then become targets for natural killer cells.
Recently, the regulation of TAP by phosphorylation was
examined (89). Phosphorylated TAP complexes can bind
ATP and peptides but are not capable of transporting
peptides. Several TAP polymorphic residues are potential
phosphorylation sites. Therefore, it was suggested that
abnormal TAP phosphorylation leads to cytotoxic immune responses and subsequent development of certain
autoimmune diseases, which are known to have associations with TAP polymorphism.
MHC class I molecules are not only critical mediators
in host defense against intracellular pathogens, but also
can stimulate strong alloreactions against transplanted
tissue. The incidence and severity of acute rejection after
renal transplantations seem to be influenced by TAP2
gene polymorphism (81). It appears that donor’s antigen
presenting cells with the TAP2*0103 allele have attenuated efficacy in the presentation of allospecific antigens to
Physiol Rev • VOL
the recipient’s T cells, but further investigations are necessary to evaluate the significance of the TAP complex in
rejection after transplantations.
D. TAP Deficiency and Tumor Development
Many tumors escape recognition by CTLs. In some
cancers, including melanomas, this has been associated
with ineffective antigen processing and presentation of
tumor-specific peptides because of low levels of MHC
class I molecules (144, 146). In tumor cell lines from
breast cancer (5) or human small cell lung cancer (144),
low to nondetectable levels of TAP1 and/or TAP2 mRNA
were found, which can be restored by IFN-␥. In murine as
well as human cancers, a downregulation of TAP1 expression by an unknown mechanism or a mutation of TAP
resulting in a loss or decrease in class I surface expression has been demonstrated (25, 128, 143). In some malignant tumor cells, the reduced levels of TAP mRNA
could be restored by IFN-␥ stimulation (143). One type of
human tumor characterized by more than one group of
investigators is breast carcinomas. TAP1 downregulation
was found in 13 and 44% of the lesions (73, 174). The
variations in the results may be determined by characteristics of the patients, the tumor type, or the proliferative
status. The frequency of TAP2 downregulation correlates
with that of TAP1 but was rarely examined. The mRNA
levels of TAP1 and TAP2 can be restored by treatment
with IFN-␥. Recently, it was observed in metastatic melanoma cells that, despite an increase in TAP1 and TAP2
mRNA levels by IFN-␥, a similar increase in cytotoxicity
did not occur (108).
The downregulation of TAP in several tumor cell
lines can be corrected by transfection with the wild-type
form or the treatment with several cytokines, such as
IFN-␥ and TNF-␣. The phenotypic changes are accompanied by an increase in MHC class I expression. Recently,
in a small cell lung carcinoma cell line the potential of
providing exogenous TAP in cancer therapies was tested
(5). With vaccinia virus containing the TAP1 gene, it could
be shown that this virus could reduce tumors in mice and,
therefore, TAP should be considered for inclusion in cancer therapies. In contrast to the above-mentioned cytokines, interleukin-10 leads to TAP downregulation and
subsequently to a reduced cell surface expression of class
I antigens (184). This fact may be of clinical relevance,
since a large number of human tumors secrete interleukin-10.
Downregulation of TAP expression and, thereby, loss
of surface HLA class I molecules, can be a tumor escape
mechanism, but also mutations in the TAP genes, as
shown for example for TAP1 in a small cell lung cancer
(25). This mutation introduces an amino acid exchange at
position 659 in TAP1, resulting in a nonfunctional TAP1
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In genetic diseases, not only TAP2, but also TAP1
may be involved. In one patient suffering type 1 BLS, a
splice site mutation in the TAP1 gene was described (44).
Interestingly, TAP2 protein was undetectable. Two other
patients, displaying not only the typical lung syndrome of
MHC class I deficiency but also skin lesions, were found
to be deficient of TAP1 (35). In both cases, mutations
introducing a frame shift into the first third of the coding
sequence were observed. The syndromes associated with
TAP1 and TAP2 deficiency are similar and are characterized by the development of chronic inflammation of the
respiratory tract in late childhood and vasculitis at variable stages, but deficiency of TAP is compatible with life.
In later stages, recurrent bacterial infections may lead to
progressive lung damage, respiratory failure, and death.
Early recognition, treatment of the respiratory infections,
and cleansing of skin ulcers of TAP-deficient patients are
the major aims of therapy. Surgical intervention for
chronic sinusitis seems to promote progression of nasal
disease leading to bronchial infections; immunosuppressive and immunomodulatory treatments are associated
with progression of skin lesions (45). Due to the ubiquitous tissue distribution of MHC class I molecules, a gene
therapy of TAP-deficiency syndrome may not be practicable.
INTRACELLULAR PEPTIDE TRANSPORT IN ANTIGEN PROCESSING
VIII. CONCLUDING REMARKS
The TAP peptide transporters are a key link between
antigen processing and presentation. The evaluation of its
molecular structure and function will contribute to the
understanding of (patho)physiological processes in which
the TAP complex may be involved. However, many questions remain open to fully understand the whole process
of T-cell immunity, especially regarding the mechanisms
governing peptide binding to MHC class I molecules in the
ER. On one level, the process seems to represent a complex folding event; on another level it is a highly regulated
system ensuring the surface expression of high-affinity
MHC class I-peptide complexes. These complexes are
essential for CD8⫹ T cell-mediated immunity. The elucidation of all steps in the antigen presentation pathway is
Physiol Rev • VOL
essential for many new therapeutic approaches in different diseases. Knowledge about the molecular mechanisms of how viruses evade the immune defense will
identify novel pathogenic factors and will probably allow
the development of new vaccination strategies. Moreover,
studies have revealed that loss of TAP function occurs
more often in metastatic than in primary tumors. The
ability of tumor cells to evade T-cell responses has important implications for the understanding of tumorigenesis. The potential efficacy of immunotherapy for cancer
is dependent on our knowledge of the underlying mechanisms. If mutations in TAP function allow tumor cells to
escape immune surveillance, this may have implications
in the therapeutic strategies. Further analysis will clarify
the interaction of malignant cells with the immune system
of the host and the significance of the loss of TAP function.
The Deutsche Forschungsgemeinschaft funded this research.
Address for reprint requests and other correspondence: R.
Tampé, Institut für Biochemie, Biozentrum Frankfurt, GoetheUniversität Frankfurt, Marie-Curie-Str. 9, D-60439 Frankfurt
a.M., Germany (E-mail: [email protected]).
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protein. MHC class I molecule expression on the cell
surface could be restored by expression of wild-type
TAP1 or addition of exogenous peptides. The mutation of
TAP1 is located between the C loop and the Walker B
motif, indicating that this mutation might affect ATP binding or hydrolysis. Interestingly, mutations that affect
TAP1 occur frequently in a variety of human tumors, for
example, in primary breast cancer (73, 174). The expression of TAP1 in carcinoma lesions was significantly associated with tumor grading and reduced survival. Like
normal mammary tissue, low-grade breast carcinoma lesions showed no reduced TAP1 protein (174). A similar
situation was found for colorectal carcinomas (74),
whereas adenomas and normal mucose tissue always exhibit no loss of TAP1.
Even if some studies correlate the presence of deficiencies in the MHC class I antigen processing pathway
with tumor progression (73, 144, 174), it is still unclear
whether these deficits have any consequence for tumor
development. To clarify this point, matched panels of
TAP1-positive and TAP1-negative tumor cell lines were
generated (71). Inoculation of mice with TAP1-negative
cells produced large and persistent tumors, whereas in
contrast, TAP1-positive cells did not generate lasting tumors. In athymic mice, both cell lines produced tumors,
confirming that TAP-dependent differences in tumorigenicity were due to T cell-dependent immune responses. It
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