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82
CD4 and CD8: modulators of T-cell receptor recognition of
antigen and of immune responses?
Rose Zamoyska
The response of T cells to antigen involves the participation
of a number of distinct receptor-ligand engagements. The
major players in the recognition of complexes of major
histocompatibility complex molecules and peptide antigens
are the T-cell receptors and the co-receptors CD4 and CDS.
Progress in understanding the physical structures of these
molecules, and how complexes between them are formed,
is helping our understanding of how they participate in
regulating the signals transduced to T cells.
Address
Molecular Immunology, National Institute for Medical Research, The
Ridgeway, London NW7 1AA, UK; e-mail [email protected]
Current Opinion in Immunology 1998, 10:82-87
http:llbiomednet.comlelecref/O952791501000089
© Current Biology Ltd ISSN 0952-7915
Abbreviations
APL
alteredpeptide ligand
CDR
complementaritydetermining region
MHC
majorhistocompatibilitycomplex
TCR
T-cell receptor
Tg-TCR transgene-encodedT-cell receptor
Introduction
T h e cell-surface glycoproteins CD4 and CD8 were
initially described as specific markers of peripheral T cells
with distinct effector functions; CD4 was found to be
expressed by M H C class II-restricted helper T cells and
CD8 by M H C class I-restricted cytotoxic T cells [1].
Subsequently, CD4 and CD8 were themselves shown to
be receptors for M H C molecules and mutational analysis
established that the binding sites for CD4 [2,3] and for
CD8 [4,5] mapped to structurally similar regions of the
constant domains of M H C class II and class I molecules,
respectively. T h e observation that the binding sites for
CD4 and CD8 on M H C molecules were separate from the
peptide-binding domain of M H C molecules and therefore,
from the site of interaction with the T-cell receptor
(TCR), suggested a single M H C molecule could be bound
simultaneously by both T C R and CD4 or CD8, increasing
the overall avidity of the interaction. In addition, it was
discovered that the cytoplasmic domains of CD4 and
CD8 were associated with a T-cell-specific intracellular
protein tyrosine kinase, p56 lck (Lck) [6,7]. Lck is a Src
family kinase whose activity is critical for initiation of the
intracellular tyrosine kinase cascade in response to T C R
triggering [8]. Thus, the simultaneous binding of CD4
or CD8 to the same M H C complex as the T C R could
juxtapose Lck and the TCR, leading to increased tyrosine
phosphorylation and further recruitment and activation of
downstream signalling effector molecules [9°]. Indeed it
was shown that co-ligating CD4 or CD8 to the T C R
provided a more potent stimulus than simply ligating
T C R alone [10-12] giving rise to the hypothesis that
CD4 and CD8 acted as co-receptors in concert with the
antigen-specific T C R for recognition of peptide-MHC
complexes [131.
A current preoccupation of biologists studying T cells is
how recognition of M H C - p e p t i d e ligands by receptors on
T cells can induce a number of distinct outcomes during
differentiation and activation of mature T cells [14°,15"].
It is clear that involvement of the co-receptor can have
a significant influence on the outcome of p e p t i d e - M H C
engagement. What is less clear, is precisely how these
effects are mediated. Recent controversies have focused
on whether the primary role of the co-receptors is to
augment the relatively weak affinity of the T C R for MHC
molecules, or whether it is mainly to recruit sufficient
Lck to the signalling complex in order to trigger the
response. With the advance of technologies that allow
direct measurement of affinities and stabilities of these
intermolecular interactions, we are making progress in
assessing the contributions of the individual components
to the formation of stable complexes necessary for signal
transduction. Furthermore, progress in solving crystal
structures of the individual components of the T C R
signalling machinery, together with structural determination of complexes between some of the individual
components, is leading to a greater understanding of
how these structures interact. However, while these
biophysical measurements help us to understand the
basics of these interactions, they have yet to explain
how these receptor-ligand engagements lead to diverse
outcomes. Here I review some of the more recent findings
that bear on these questions.
TCR-co-receptor
structures and the
recognition of antigen-MHC
complexes
Despite the fact that CD4 and CD8 interact with
structurally homologous sites on their M H C ligands,
they have very little in common. Although both use
basic immunoglobulin domains for their ligand-binding
structures, these are arranged quite differently in the
two molecules. CD4 is a single polypeptide, folded into
four external immunoglobulin-related domains, that has
a unique strand topology between domains 1 and 2 (D1
and D2) and between domains 3 and 4 (D3 and D4),
as elucidated in the crystal structure of a human D1D2
fragment [16,17] and of rat D3D4 fragment [18]. T h e
recently solved structure of the entire external portion
of CD4 [19 ° ] has added to our understanding of this
CD4 and CD8 and immune responses Zamoyska
molecule by indicating significant flexibility between D2
and D3 and a tendency of the molecule to dimerise at
high protein concentrations, through interactions between
opposing D4 domains. T h e local concentration of CD4
would be expected to increase in the area of contact
between a T cell and antigen-presenting cell; therefore,
the ability to dimerise may be particularly important if the
T C R complex needs to form lattices for successful signal
transduction. Several reports indicate that optimal signal
transduction occurs when T C R and CD4 form stable
associations with each other [13] and there are indications
that T C R s themselves can oligomerise upon binding
M H C - p e p t i d e complexes [20°°]. Thus dimerisation of two
CD4, or two TCR, molecules, as well as interactions
between CD4 and TCR, may be important in signal
transduction. Chimaeric CD4 molecules, in which human
D3 and D4 domains were substituted for their mouse
counterparts, were shown to act in a dominant negative
fashion, interfering with wild-type CD4 function [21°].
T h e s e data were interpreted as a failure of these chimaeric
CD4s to form a close association with the T C R , as
demonstrated by a decrease in fluorescent resonance
energy transfer between the hybrid CD4 and TCR.
However, it is also possible that human and mouse D4
domains fail to dimerise efficiently, which may in part
explain why these hybrid molecules were so efficient at
disrupting productive signal transduction elicited by a
wild-type CD4 molecule.
CD8, by contrast, is a disulphide-bonded heterodimer of
two polypeptides, cx and 13, encoded by distinct genes
that are physically linked and are predicted to show
conserved overall structural topology although they share
only -20% residue identity [22]. Both polypeptides have
an immunoglobulin-like amino-terminal domain linked to
the transmembrane domain by an extended polypeptide
region that contains a number of O-linked sugars.
Currently, the available crystal structure information
is for CD8occx homodimers, which indicates that the
amino-terminal immunogiobulin-like domains fold very
similarly to an Fv-like homodimer [23]. More recently,
the structure of a complex between CD8 and HLA-A2
has been solved; this structure confirms mutagenesis
studies that the major binding interface between these
two molecules occurs between a highly flexible loop in
the 0.3 domain of M H C class I (residues 223-229) that
is clamped between the CDR1- and CDR3-1ike loops
from both the CD8 subunits [24°°]. Surprisingly, the
contribution of the two CD8 subunits to the interaction
is not equivalent, with -70% of the solvent-accessible
area of the CD8otl domain interacting with parts of the
HLA-A2 or2 domain and I~z-microglobulin, in addition to
the cx3 domain interactions. This structure is unlikely to
form interactions with more than one M H C molecule as
had been speculated; however, a similar latticing to that
postulated for CD4 could occur, as the existence of CD8
multimers has been described [25], formed between free
cysteine residues in the hinge region.
83
Although CD8 can form cxa homodimers, the major
species expressed on the surface of mature M H C class
I-restricted T cells is a heterodimer of et and 13.
CD8~ null mice develop only -20% of the normal numbers
of peripheral CD8 ÷ cells, indicating that the CD81~
polypeptide supplies a unique function [26,27]. Although
the cytoplasmic domain of the 13 polypeptide does not
interact with Lck, there have been suggestions that
the CD8I] polypeptide can modify CD8-associated Lck
activity [28]. There are clear indications that, although
the heterodimer and homodimer have similar affinity for
M H C [29°'], the heterodimer has a more significant effect
in influencing the binding of T C R to M H C [29°',30°'].
Furthermore, in a series of confocal studies we have shown
that anti-CD813 antibodies are significantly more efficient
than anti-CD8a antibodies at inducing co-capping of
the T C R (Kwan Lim et al. unpublished data; see Note
added in proof), suggesting that antibodies to the CD813
polypeptide may preferentially promote a conformation
of CD8 that stabilises an association with the TCR,
independently of their binding to MHC.
Further examples of dynamic interactions between TCRs,
co-receptors and their M H C - p e p t i d e ligands have been
provided in a series of studies which showed that minimal
occupancy of the T C R increased the capacity of CD8
to bind M H C molecules [31]. This suggests that ligation
of the T C R can promote binding of CD8, resulting
in an overall avidity and dissociation kinetics which
exceeds the sum of the individual affinities. Indeed there
appear to be preferred conformational states which are
stabilised by both T C R and CD8 being bound to the
same M H C molecule [29°°,32]. On the T-cell surface
these interactions may be further promoted by cytoskeletal
rearrangements that redistribute the molecules to areas
of interaction with the MHC, as agents that disrupt
cytoskeletal function have been shown to disrupt CD8
binding to M H C class I [33].
Role of the co-receptors during differentiation
T h e co-receptors have a significant role during T-cell differentiation, as mice that lack expression of CD4 (CD4 null)
[34] or CD8(CD8 null) [35] have severely impaired differentiation of M H C class II- and class I-restricted T
cells, respectively. For both CD4 [36] and CD8 [37],
if the endogenous molecules are replaced by mutants
that lack cytoplasmic domains, differentiation of these
subpopulations is somewhat restored, although, characteristically, high levels of expression of such tailless molecules
are required. These results suggest that the Lck-binding
function of the co-receptors is not an absolute requirement
for the function of these molecules during differentiation,
although the T-cell repertoire that develops in these mice
may well be altered. It has now been confirmed that
T-cell differentiation can occur in the absence of CD4
and CD8 expression, implying that the co-receptors do not
contribute a unique differentiation signal. Thus, a small
subpopulation of CD4--CD8- double (DN) negative cells,
84
Antigenrecognition
with T-helper phenotype was shown to differentiate in
CD4 null mice [34], although no equivalent population with
cytotoxic phenotype could be demonstrated in CD8 null
mice [35]. However, in CD8 null mice expressing class
I-restricted transgenic TCRs (Tg-TCR), the differentiation of T C R ÷ double-negative cells with cytolytic function
could be induced by culture of foetal thymus lobes
with peptides that were weakly stimulatory for CD8 ÷
Tg-TCR-expressing cells [38°,39°]. These data argue that
although the co-receptors may not provide a unique
signal to direct differentiation to the individual lineages,
during normal differentiation they provide a significant
contribution to the selection of a broad T C R repertoire
on endogenous thymic MHC-peptide ligands.
Contribution of the co-receptors to anergy
versus activation and to differentiation of
effector T cell subsets
In addition to their ability to alter the dynamics of
TCR-ligand binding, recent evidence has shown that
the co-receptors can have a significant influence on the
outcome of antigen engagement. It had been shown
previously that expression of co-receptors could influence
the fine specificity of a response. For example, co-receptornegative T cells that were responsive to particular antigens
could broaden their recognition and acquire the ability
to respond to related antigens once transfected with the
appropriate co-receptor [40,41]. It has now been shown
that a co-receptor involvement can have a significant
influence on the nature of the ensuing response.
While some peptide antigens are able to stimulate
full activation of T cells, there are variant peptides,
generally referred to as altered peptide ligands (APLs),
that stimulate partial responses. These peptides may be
weak agonists or may be fully antagonistic and drive the
cells into an anergic state [14°]. It had been shown that for
class I-restricted cells, CD8 blockade can convert a poor
antagonist to a good antagonist [42], and that expression
of the CD813 chain can influence whether a particular
APL is seen as an agonist or partial agonist [43]. Similarly,
reduction in the level of CD4 can change a partial or weak
agonist into an antagonist [44,45]. It has now been shown
that the co-receptor has a more direct influence on the
nature of the signal that is transduced upon encounter
with antigen. Madrenas et al. [46"'] found that if they
stimulated a T-cell clone in the presence of anti-CD4
antibody or with mutant MHC class II molecules that fail
to interact with CD4, they could change a characteristic
pattern of tyrosine phosphorylation seen after stimulation
with agonist peptides to that resembling the pattern found
upon encounter with antagonist peptides. These data
suggest that involvement of the co-receptor in recruiting
Lck to the T C R complex can have a significant influence on the activation of specific intracellular signalling
pathways. A practical consequence of this has been
known for some time: non-depleting anti-CD4 antibodies
function as efficient immune modulators in vivo capable of
generating long-lasting transplantation tolerance [47-49].
Furthermore, a similar effect has been described recently
for non-stimulatory anti-CD3 antibodies [50"']. Such
reagents are able to engage the T C R without co-localising
the co-receptor and appear to induce a state of anergy in
T cells similar to that induced by antagonistic peptides.
In addition to influencing whether a cell may be anergised
or activated in response to peptide, the involvement of
CD4 can influence the nature of the T-cell response
elicited by antigen. A recent study by Foweli et al.
[51"'] showed that in CD4null mice, only T h l responses
were stimulated by pathogens such as Nippostrongylus
brasiliensis that generally preferentially stimulate a Th2
response. This change was not simply due to an altered
T C R repertoire in these animals; in the same study, a
significant difference on the ability of CD4 ÷ and CD4cells expressing the same T g - T C R to differentiate into
Th2 cells was shown. In the absence of CD4 interaction
with MHC class II, the T cells appear to alter the
balance of cytokines they produce; in particular, they fail
to produce interleukin 4 (IL-4), causing differentiation to
be pushed exclusively towards the T h l lineage. It thus
seems that there are a number of subtle influences that
the co-receptors can have on the nature of the response,
both by influencing the sensitivity of antigen recognition
and potentially the precise nature of the response.
Co-receptor dependence in T-cell activation
It has long been recognised that some T cells require
active participation of the co-receptor to initiate a
productive response to antigen, while others appear to be
activated independently of the co-receptor. Co-receptor
independence was initially defined as the resistance of
some T-cell clones to inhibition by anti-CD4 and CD8
antibodies [13]. Such antibody blocking studies were
complicated by the observation that, in addition to the
antibody preventing the co-receptor binding the MHC
molecule, engagement of the co-receptors by antibody
could generate an inhibitory or negative signal [13]. The
latter was thought to occur through the activation of
Lck. Nevertheless, it was subsequently shown that if
individual TCRs were expressed in the absence of the
co-receptors, either in hybridomas or T-cell clones, in
general co-receptor-independent TCRs would respond to
antigen while co-receptor-dependent TCRs would not
[41,52].
The property of co-receptor dependence was thought to
reflect the affinity of the T C R for its ligand and it has
certainly been shown to be an inherent property of the
TCR. For example, transgenic mice made from an alloreactive CD8-dependent or -independent T C R retained this
phenotype in their cytotoxic lymphocyte precursors [53].
However, there appear to be differences in the efficiency
of signal transduction between CD8-dependent and -independent TCRs which are unrelated to their affinity for
peptide-MHC complexes. Thus, we showed that a variety
CD4 and CD8 and immune responses Zamoyska
85
of CD8-independent hybridomas had markedly increased
sensitivity to stimulation with anti-CD3 antibodies than
a comparable panel of CD8-dependent hybridomas [52],
a property that is unlikely to be related to their affinity
for antigen. Furthermore, Yelon et al. [54] found that
CD4 cells expressing a T g - T C R showed considerable
CD4 dependency as immature thymocytes, which became
less marked when they became peripheral T cells. When
repeatedly stimulated to create a long-term line, the same
Tg-TCR-expressing cells acquired a CD4-independent
phenotype. We observed a similar progression from CD8
dependence to CD8 independence after repeated stimulation of a class I-restricted T C R line from a transgenic
mouse mutant for the RAG-1 gene, which confirms that
this progression to co-receptor independence involves only
the T g - T C R (G Kwan-Lim, R Zamoyska, unpublished
data). Given that the T C R from these transgenic animals
would be of the same affinity at all stages of maturation
and stimulation, the change to co-receptor independence
must reflect an alteration in the sensitivity of the T cell to
stimulation.
soluble ligands and a single receptor species, stimulation of
T cells requires the binding of a number of unassociated
and unrelated molecules. Despite this, similar questions
arise of how extracellular engagement of surface molecules
is able to transmit a signal into the cell. Receptor signalling
is envisaged to occur in two principal ways, either by
receptor aggregation initiating trans-activation of signalling
domains or by conformational changes resulting from
receptor-ligand binding directly relaying activation signals
inside the cell. T h e data which are accumulating on
the interactions between T C R s and co-receptors and
M H C molecules suggest that, for T cells, both types
of interactions are important. It seems likely that for
successful signal transduction, aggregation of distinct
receptor species may be facilitated by conformational
changes that stabilise these interactions. We are beginning
to gain an understanding of the subtleties involved in
receptor-ligand engagements on T cells which will be
of benefit in designing strategies for regulating immune
responses in the future.
Recently, Anel et al. [55"] have compared the tyrosine
phosphorylation patterns induced by stimulation with
antigen or anti-CD3 antibody in cytotoxic lymphocyte-precursors and clones expressing either a CD8-dependent or
-independent TCR. T h e y concluded that the intensity
and duration of the signal induced by T C R engagement
was greater in CD8-independent clones, even when
stimulation was with anti-CD3 antibody and therefore was
unlikely to be simply a reflection of the affinity of the T C R
for MHC. An intriguing observation noted by ourselves
and by Anel et al., [52,55"] was that CD8-dependent
T C R s seem to be expressed in greater abundance than
CD8-independent TCRs, on the surface of T cells, and
it will be interesting to explore whether this is linked to
their different behaviour with respect to the co-receptors.
It is interesting to note that the crystal structure of
the T C R utilised in Anel et al.'s study (KB5-C20),
Which is remarkably CD8 dependent, has been solved
recently [56 °° ] and differs from previously published
crystal structures of the T C R s 2C [57] and A6 [58] in that it
has a very long CDR31~ loop. Furthermore, whereas both
2C and A6 present relatively flat surfaces for interaction
with the M H C - p e p t i d e complex, KB5-C20 does not.
Therefore, it is postulated that KB5-C20 will have to
undergo significant conformational change when binding
M H C - p e p t i d e ligands, which may explain its dependence
on CD8 for this interaction. It will be interesting to see
whether the structures of other co-receptor-dependent and
-independent T C R s will be so diverse.
T h e citation which appears as (Kwan Lim et al., unpublished data) has now been accepted for publication [59].
Note added in proof
Acknowledgements
l thank my colleagues Gitta Stockinger, Albert Basson and Paul Travers
for their helpful comments on the manuscript and the Medical Research
Council for their support.
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