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1182 Part IX: Lymphocytes and Plasma Cells Chapter 76: Functions of T Lymphocytes: T-cell Receptors for Antigen 1183

T-cell populations maintain the ability to both survive independently T-CELL ACCESSORY MOLECULES
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of cognate antigen and self-renew in response to external homeo-
static signals such as IL-15 and IL-7, hence maintaining themselves
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at stable levels for many years. In addition, they have less-stringent IMMUNE MODULATORY MOLECULES
requirements for activation and an enhanced capacity for lymphok- CD28
ine production upon rechallenge with the same antigen, and require a CD28 is a 44-kDa disulfide-linked homodimer that is expressed on most
lower level of costimulatory factors. resting T cells and plasma cells. Mature thymocytes have higher levels
Memory CD4+ or CD8+ T lymphocytes can also be distinguished of CD28 than immature cells. Among human peripheral T cells, more
from naïve cells based on their surface phenotypes of CD45 isoforms, than 90 percent of CD4+ T cells and approximately 50 percent of CD8
rate of cycling, and migration. CD45, also known as leukocyte common T cells express CD28. In general, activation of T cells induces enhanced
antigen or T200, consists of a family of membrane glycoproteins, rang- expression of CD28, but ligation of CD28 leads to its transient downreg-
ing from 180 to 220 kDa, that are expressed on all leukocytes. Each ulation. CD28 is another member of the immunoglobulin superfam-
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member is the product of a single complex gene on chromosome 1 that ily and binds to both CD80 and CD86 using a highly conserved motif
contains 34 exons. Exons 3 through 7 may be spliced differently at the (MYPPPY) in a loop that resembles the third complementarity-deter-
RNA transcript level to generate several distinct messenger RNA and mining region of immunoglobulin molecules. CD28 binds to CD80 with
protein products. The deduced amino acid sequences of these protein relatively low affinity (dissociation constant [Kd] = 4 μM) and dissoci-
products have extracellular domains ranging from 391 to 552 amino ates very rapidly (K = 1.6 s ), and its binding to CD86 may be even
−1 107
off
acids, a transmembrane region, and a highly conserved cytoplasmic weaker. 108
domain of 705 amino acids. This large cytoplasmic domain contains an CD28 functions as a major costimulatory molecules that is
intrinsic tyrosine phosphatase activity that is important in the regula- essential for T-cell activation, probably in the context of TCR/CD28
tion of various activation pathways involving tyrosine kinase activity, microcluster formation. Ligation of CD28 by CD80 or CD86 or
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such as those involved in signal transduction via the TCR for antigen. by anti-CD28 antibodies activates distinct signaling pathways that
Different isoforms of CD45, designated as CD45R, have distinct expres- function together with the signals induced by ligation of the TCR to
sion patterns during lymphocyte ontogeny and activation. Therefore, allow for T-cell activation and proliferation. Following coligation
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cell subsets can be readily characterized by flow cytometry approaches of CD28, the Src kinases Lck and Fyn may phosphorylate a tyrosine
using specific monoclonal antibodies. Naïve CD4+ T cells express within an ITAM found in the cytoplasmic domain of CD28, allowing
CD45RA, whereas memory CD4+ T cells and CD8+ T cells express the latter to bind and to activate phosphatidylinositide 3-kinase via its
CD45RO. CD45RB can also be useful for distinguishing memory SH2 domains. CD28 signaling also facilitates GTP/guanosine diphos-
T cells. Within the CD4+ memory T-cell population, for example, phate (GDP) exchange on Ras, resulting in activation of the MAP
there is an increase of helper activity associated with the shift from a kinase pathway, activation of Akt kinase, and activation of the adapter
CD45RB bright to a CD45RB phenotype. 101 protein Vav and the associated Rac pathway. These signals enhance
dim
In addition, the distinct expression of chemokine receptors the transcription of IL-2 and the stability of IL-2 transcripts, thereby
(CCRs) or homing molecules can be used to characterize T-cell sub- stimulating T-cell proliferation. Although mice lacking CD28 can
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sets: relative to naïve T cells, memory T cells express lower levels of mount effective T-cell responses, they are defective in T-cell–depen-
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L-selectin (CD62L) and higher levels of CD29 and CD44. More dent antibody responses, suggesting that CD28 is necessary for T-cell–
recent studies demonstrate that memory cells can be further subdi- B-cell interactions and the proficient generation of antibody responses
vided into CD44+CD62L+CCR7+ central memory T cells (T cells) to antigen. 112
CM
and CD44+CD62L−CCR7− effector memory T cells (T cells). The requirement for the same cell to present both the specific anti-
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EM
Because of their constitutive expression of CCR7 and CD62L, T gen and the costimulatory signal is crucial to prevent destructive auto-
CM
cells home to secondary lymphoid organs, where they have little or immune responses to self-tissues. This restricts the initiation of T-cell
no immediate effector function, but show greater sensitivity to anti- responses to APCs that express both the peptide antigen in the con-
genic stimulation in comparison to naïve T cells, are less dependent text of self-MHC molecules and the ligands for CD28, namely, CD80
on costimulation, and upregulate CD40L to a greater extent. However, and CD86. This is particularly important as not all self-reactive T cells
upon recognition of their cognate antigen, they have a high prolifera- undergo deletion in the thymus because not all self-peptides are pre-
tive potential and can rapidly differentiate into large numbers of effec- sented in the thymus (Chap. 6). This is especially true for specialized
tor cells. T cells, in contrast, have higher migratory potential and tissues that express proteins that are never expressed in the thymus.
EM
display immediate effector function. Therefore, T cells are predom- If simultaneous ligation of the TCR and CD28 was not required, then
CM
inantly found in the CD4 lineage and are enriched in lymph nodes T cells that recognize the self-peptide expressed by the MHC of such
and tonsils, whereas T cells are more frequent in the CD8 compart- specialized tissues could become activated, leading to autoimmune
EM
ment in lung, liver, and intestines. Accordingly, CD8+ T cells carry rejection of the specialized tissue. Instead, ligation of the TCR in the
EM
large amounts of perforin, and both CD4+ and CD8+ T cells can absence of CD28 ligation leads to a state of hyporesponsiveness or
EM
produce IFN-γ, IL-4, and IL-5 within hours after following antigenic anergy, in which the T cell expressing that receptor becomes refrac-
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stimulation. tory to activation. Anergized T-cell clones produce only negligible
It has long been controversial whether memory T cells arise dur- amounts of IL-2, which is crucial for clonal expansion following T-cell
ing the contraction phase and develop directly from effector cells, or activation. Interestingly, clonal T-cell anergy was found not to be a ter-
whether they diverge early during an immune response, and arise in minal fate, as the addition of exogenous IL-2 during restimulation could
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parallel with short-lived effector cells. Recent studies, however, have reverse the phenotype. These characteristics are not limited to T cells,
provided evidence for an early delineation of the effector versus mem- as anergic B cells also demonstrate some of the hallmark features, such
ory T-cell fates regulated through specific transcription factors and as reduced proliferation and effector function. Anergy is an important
cytokines, such as IL-7 receptor α-chain (IL-7R) expression, IL-2, IL-12, basis for development of peripheral tolerance for self-antigens that are
and T-BET, EOMES, and BLIMP-1. 104,105 not expressed in the thymus (Chaps. 6 and 74).

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