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CONCISE REVIEWS
OF
PEDIATRIC INFECTIOUS DISEASES®
CONTENTS
T Cell Immunology for the Clinician
EDITORIAL BOARD
Co-Editors: Margaret C. Fisher, MD, and Gary D. Overturf, MD
Editors for this Issue: Geoffrey A. Weinberg, MD
Board Members
Michael Cappello, MD
Ellen G. Chadwick, MD
Janet A. Englund, MD
Leonard R. Krilov, MD
Charles T. Leach, MD
Kathleen McGann, MD
Jennifer Read, MD
Jeffrey R. Starke, MD
Geoffrey A. Weinberg, MD
Leonard Weiner, MD
Charles R. Woods, MD
T Cell Immunology for the Clinician
Jennifer L. Nayak, MD,* and Andrea J. Sant, PhD†
Key Words: T cells, cell-mediated immunity,
immunodeficiency
(Pediatr Infect Dis J 2011;30: 248 –250)
T
he adaptive immune system is characterized by its ability to distinguish self from
nonself; responds specifically to encounters
with foreign antigens (eg, pathogens); and
develops immunologic memory allowing for
a more vigorous response to subsequent
challenges with the same antigen. T lymphocytes play several roles in adaptive immunity,
autoimmune disease, and allergy; new
T-helper cell subsets continue to be described,
promising to better explain autoimmune and
primary immunodeficiency diseases.1– 6
T CELL DEVELOPMENT
Bone marrow pluripotent hematopoietic stem cells first give rise to multipotent,
then to common, lymphoid progenitor cells;
some of the latter further traffic to the thymus for T-cell lymphocyte differentiation.1–3
T cells are marked by the presence of the
surface-expressed heterodimeric T-cell receptor (TCR) that consists of combinations
of either the ␣ and ␤, or the ␥ and ␦ chains.
The germline TCR genes contain multiple
variable (V), diversity (D) (in ␤ and ␥
genes), and joining (J) segments. The V(D)J
recombinase enzyme complex (including enzymes encoded by the RAG1, RAG2, and
From the Departments of *Pediatrics and †Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Copyright © 2011 by Lippincott Williams & Wilkins
ISSN: 0891-3668/11/3003-0248
DOI: 10.1097/INF.0b013e3182074658
Artemis genes, among others) mediates
cleavage and repair of DNA near the V, D,
and J segments in a series of coordinated
steps. If the gene recombination is productive and the RNA message has no abnormal
stop codons present, the subsequently translated protein chains pair to form the TCR,
which is expressed on the cell surface. Similar to immunoglobulin gene rearrangement,
tremendous TCR-binding site diversity results from this process—the large number of
possible recombinations of V, D, and J segments provide combinatorial diversity, and
additional diversity is conferred by imprecision in the DNA-joining reaction.2,3,7
The maturing T cells can be divided
into 2 groups depending on the cluster of
differentiation, or CD, surface markers expressed. If an ␣␤ TCR is expressed at the cell
surface, the cell first transitions to a “double
positive” T cell, expressing both the CD4
and CD8 surface markers. The T cell then
undergoes the 2 thymic processes of positive
and negative selection (Fig. 1). Positive selection occurs when the TCR binds, with low
avidity, to a major histocompatibility (MHC)
molecule presenting a self-peptide. T cells
that are not able to bind strongly enough to
these self-peptide-MHC complexes are eliminated by apoptosis (“death by neglect”).
Cells positively selected by an MHC class I
molecule become CD8 single-positive, while
cells selected through MHC class II molecules become CD4 single-positive. Negative
selection occurs when a TCR binds with too
great avidity to the self-peptide-MHC; these
cells are eliminated to ensure that potentially
autoreactive T cells do not persist.2,3 Negative selection is carried out under the control
of the AIRE (autoimmune regulator) tran-
scription factor of thymic medullary epithelial cells.8,9
ANTIGEN RECOGNITION BY T
LYMPHOCYTES
T cells respond to peptide antigens
bound to MHC molecules; the peptide antigens are either produced in or taken up by
the body’s own cells. CD8⫹ T cells are the
cytotoxic T cells of the adaptive immune
system. They respond to peptides that are 8
to 10 amino acids in length bound specifically to the peptide-binding groove of MHC
class I molecules. The MHC class I molecule
is expressed on all nucleated cells in the
body. In contrast, CD4⫹ T cells respond to
peptides presented by MHC class II molecules, which are only expressed on a limited
subset of host cells—the “professional” antigen-presenting cells (APCs, including B
cells, macrophages, and dendritic cells).
CD4⫹ T cells perform many accessory functions within the immune system; hence, they
are generally referred to as “helper” T cells.1
MHC molecules exhibit a vast amount
of polymorphism in their peptide-binding
pockets, and in addition, up to 6 unique
MHC class I and 12 unique MHC class II
molecules are able to be expressed simultaneously. Together with the diversity of
TCRs, this allows for the binding of the
tremendous array of pathogen and tumor cell
epitopes which the immune system may encounter.1,2,7 Although peptides presented on
MHC class I molecules typically are derived
from intracellular and nuclear proteins (eg,
from intracellular viral infection), certain
dendritic cells have the ability to “crosspresent” antigens derived from extracellular
The Concise Reviews of Pediatric Infectious Diseases (CRPIDS) topics, authors, and contents are chosen and approved independently by the Editorial Board of CRPIDS.
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The Pediatric Infectious Disease Journal • Volume 30, Number 3, March 2011
The Pediatric Infectious Disease Journal • Volume 30, Number 3, March 2011
FIGURE 1. Summary of ␣␤ T-cell receptor (TCR)-expressing T cell development in
the thymus.
sources to CD8⫹ T cells. This allows naive
cytotoxic CD8⫹ lymphocytes to be activated
even when a pathogen does not cause an
intracellular infection in APCs, or when a
tumor is not APC-derived.10 Similarly, although class II MHC molecules are classically described as presenting peptides imported from the cell surface (eg, from
extracellular infection), more recent data
demonstrate that the process of autophagy
allows intracellular and nuclear pathogens to
also access the endosomal network and be
presented to CD4⫹ T cells through MHC
class II molecules.11
T LYMPHOCYTE EFFECTOR
FUNCTIONS
CD8ⴙ T Cells
During an immune response, naive
cytotoxic CD8⫹ T cells responding to antigen undergo rapid clonal expansion within
the draining lymph node, with the resulting
generation of a large number of antigenspecific T cells. These cells can express chemokine receptors that allow them to travel to
sites of inflammation or infection. There they
bring about pathogen clearance by secreting
effector cytokines such as IFN␥ and TNF␣,
and by producing molecules that result in
direct cell contact-dependent cytolysis of target cells, including perforin and granzyme B.
After the peak of the effector phase of the
immune response, the antigen-specific CD8⫹
T-cell population contracts by apoptosis,
with only about 5% to 10% of the original
cells surviving as long-lived memory
cells.4,12,13 Especially in settings with only a
low level of inflammation, CD4⫹ T cells
help support the development of CD8⫹ Tcell effector function by multiple mechanisms, including through the maturation of
APCs and the production of IL-2.12,13 CD4⫹
T cells also play an important role in the
© 2011 Lippincott Williams & Wilkins
development of long-lived, functional CD8⫹
memory T cells.12,13 This memory has been
broadly divided into central and effector
memory. Central memory cells reside in
lymphoid organs, where they proliferate rapidly in response to antigen re-exposure, but
do not have immediate lytic function. Effector memory cells are found in nonlymphoid
tissues and are able to express immediate
lytic activity on recall. These cells can be
rapidly recalled on re-exposure to antigen,
resulting in rapid pathogen clearance.12,13
Therefore, activation of CD8⫹ cells through
antigen encounter elicits both robust effector function capable of selective pathogen
elimination at the site of infection, and the
development of specific memory cells that
are able to be rapidly mobilized upon future encounter with the original or a related
pathogen. Such immunologic memory
plays an important role in the immune
response to vaccination.
CD4ⴙ T Cells
CD4⫹ T cells provide help to B cells,
enabling both class switching and production
of high-affinity antibodies, initiate and maintain CD8⫹ T-cell responses, regulate macrophage function, and also directly mediate
pathogen clearance. CD4⫹ T cells may also
suppress the immune response to autoantigens and adjust the magnitude and persistence of immunity.5 Two decades ago, seminal research divided CD4⫹ T-cell responses
into 2 main T helper subsets (Th1 and Th2)
that could be distinguished by the secretion
of particular effector cytokines.14 Subsequent
work has defined Th17 cells, regulatory T cells
(Tregs), and follicular helper T cells (Tfh),
each distinguished by unique cytokine profiles
and transcription factor expression.6,15,16 Thelper cell lineage commitment was once
thought to be irreversible, but newer evidence
suggests that some degree of interconversion
may occur in vivo.6
Concise Reviews
Th1 cells are important in cell-mediated immune responses, and are able to make
IFN␥, TNF␣, and IL-2.2,5 Th1 cells activate
macrophages, assist in the clearance of intracellular pathogens, and mediate delayed-type
hypersensitivity responses. Cytokine production by Th1 cells is also important in B cell
class switching to immunoglobulin isotypes
that are useful for neutralization of toxins
and viruses.
Th2 cells play a central role in mediating immunity to parasitic infections.17 Inappropriate activation of this CD4⫹ T-cell
differentiation pathway has also been
strongly implicated in the development of
asthma and allergy. Cytokines produced by
Th2 cells include IL-4, IL-5, IL-9, and IL-13.
These cytokines play an important part in the
recruitment of eosinophils (IL-5) and mast
cells (IL-9). Th2 cells are also able to regulate B cell class switching to IgE; in turn, IgE
immune complexes activate recruited basophils and mast cells, resulting in their degranulation and the release of cytokines, chemokines, histamine, heparin, serotonin, and
proteases.
Th17 cells are important in clearance
of extracellular pathogens, including Candida albicans and Staphylococcus aureus,
especially from the skin and lungs. However,
Th17 cells have also been implicated in the
development of autoimmune diseases, including inflammatory bowel disease, psoriasis, multiple sclerosis and systemic lupus
erythematosus, as well as in chronic allergic
inflammatory processes such as asthma.
Th17 cells are able to produce multiple cytokines, including IL-17 (important in the
recruitment of neutrophils) and IL-22 (important in the production of antimicrobial
defensins).5,6,18
Tregs are critical for the maintenance
of self-tolerance and immune homeostasis,
promoting the contraction of the immune
response after pathogen clearance. They
function not only to prevent autoimmunity,
immune-mediated damage, and allergy, but
can also suppress antitumor immune responses and favor tumor progression.15 Generally, these cells can be classified as either
naturally occurring regulatory cells, derived
from the thymus, or inducible Tregs, formed
in the periphery under the influence of
TGF␤.2,5 Although both naturally occurring
and inducible Tregs exert suppressor functions in mice, to date only the naturally
occurring Tregs have been shown to have
this function in human beings.15 These cells
are characterized by the expression of the
CD25 surface marker and can produce TGF␤
and IL-10.2,5,6,15
Tfh travel to the B-cell areas of the
lymph nodes, where they facilitate the germinal center reaction of B cells as well as
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Concise Reviews
immunoglobulin affinity maturation and
class switching. These cells can be distinguished from other effector cells by their
expression of the chemokine receptor
CXCR5 (allowing positioning within the follicular area of the lymphoid tissue), downregulation of the CCR7 receptor (a chemokine receptor that retains cells in the T-cell
zones of the lymph nodes), and production of
IL-21. However, some authorities do not
consider Tfh cells to be a separate T-helper
cell subset, as opposed to simply a differentiated stage.16,19
T LYMPHOCYTES AND DISEASE
Defects in development T cell can result
in either immunodeficiency or autoimmunity.
Many T-cell immunodeficiency syndromes are
now known to be associated with specific problems in T cell development; others are part of
combined immunodeficiencies also affecting B
cells and/or NK cells; the pathogenesis of still
others is not yet clear.20 Most are rare autosomal recessive disorders, occurring in 1 per
100,000 live births or fewer.
The chromosome 22q11.2 deletion
syndrome (DiGeorge syndrome) causes a developmental defect of the thymus, and is an
unusually common T-cell defect, found in
approximately 1 per 5000 live births.20,21 A
large amount of phenotypic variability is
found in the disorder; individuals with complete DiGeorge syndrome have cardiac outflow tract anomalies, hypoparathyroidism,
facial dysmorphism, and profound T-cell
lymphopenia due to thymic aplasia. More
commonly, partial DiGeorge syndrome is
observed, with a much milder level of immunodeficiency consisting of only a slight
decline in T-cell numbers and normal T-cell
function.20,21
Mutations within the AIRE transcription factor gene are responsible for
the multiorgan disease known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. This autosomal recessive disorder appears to be
caused by interruption of the negative selection of T cells reactive to self-peptides,
preventing apoptosis of self-reactive T cells.
It is characterized by chronic mucocutaneous
candidiasis, hypoparathyroidism, and adrenal insufficiency along with other variable
autoimmune manifestations such as thyroiditis, type 1 diabetes, ovarian failure, alopecia,
or hepatitis.8,9,20
Some defects in the development of T
cell affect only selected subsets of T cells.
Although no isolated defects in the Th1 pathway have been discovered, defects in the
IFN␥ and IL-12 pathways, key mediators of
Th1 differentiation, have been reported, including deficiencies in the genes encoding
the IFN␥ or IL-12 receptors, the STAT1 tran-
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The Pediatric Infectious Disease Journal • Volume 30, Number 3, March 2011
scription factor, or IL-12 itself. These disorders are all uniquely characterized by an
increased susceptibility to intracellular
pathogens, especially mycobacterial infections, and sometimes Salmonella and certain
viral infections.22 Loss of Treg cell function
from FOXP3 gene mutations leads to the
immunodysregulation, polyendocrinopathy,
enteropathy, X-linked syndrome, characterized by severe diarrhea, insulin-dependent
diabetes mellitus, eczema, and often hypothyroidism, hemolytic anemia, thrombocytopenia, and neutropenia. This immunodeficiency syndrome, along with animal models
of FOXP3 deletion, provides clear evidence
of the importance of Tregs in maintaining the
homeostasis of the immune system.23 Recently, a majority of the cases of the autosomal dominant form of hyper-IgE recurrent
infection syndrome (formerly known as Job
syndrome), characterized by recurrent staphylococcal infections of the skin and lung,
chronic eczema, elevated serum IgE, joint
hyperextensibility, and dental abnormalities,
were found to be caused by mutations in the
STAT3 gene important in Th17 cell differentiation; patients with this disorder were subsequently found to have defects in Th17
cells.24,25 Dysregulation of the Tfh cell type
has been proposed to play a role in autoantibody production in antibody mediated autoimmune diseases such as SLE. This has
been suggested in both mouse and human
studies and is thought to occur by Tfh cells
providing inappropriate helper signals to self
reactive B cells.17,19 Additionally, ineffective
T cell help to B cells is thought to underlie
several
immunodeficiencies,
including
X-linked lymphoproliferative disease and common variable immunodeficiency.19,26
Finally, severe combined immunodeficiency syndromes (SCIDS) affect T cells,
either alone or in combination with B or NK
cells (eg, T⫺B⫺NK⫺ cell phenotype of ADA
deficiency, T⫺B⫹NK⫺ X-linked SCIDS
from defects in the IL2 receptor, or
T⫺B⫹NK⫹ SCIDS from defects in the IL7
receptor).20 One form of SCIDS, Omenn
syndrome, is characterized by low-to-normal
levels of T cells along with low B cells but
normal NK cells (T⫹B⫺NK⫹). Children
with Omenn syndrome have erythroderma,
chronic
diarrhea,
hepatosplenomegaly,
lymphadenopathy, eosinophilia, and elevated
serum IgE; mutations in the RAG genes impair development of T cell in the thymus,
with a resulting limited repertoire of lowaffinity T cells skewed toward a Th2 phenotype (overproduction of IL-4 and IL-5, eosinophilia, and elevated serum IgE).5,20
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© 2011 Lippincott Williams & Wilkins