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CHAPTER 76 T-LYMPHOCYTE ANTIGEN RECEPTORS

FUNCTIONS OF T T-CELL RECEPTOR HETERODIMERS
The structural basis of T-cell recognition of antigen has been known
LYMPHOCYTES: T-CELL since the 1990s, when a plethora of studies demonstrated that the pro-
teins of the T-cell antigen receptor are structurally related to immuno-
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RECEPTORS FOR ANTIGEN globulin molecules. The T-cell receptor is formed by a heterodimer,
that is, two disulfide-bond-linked polypeptides that are expressed on the
cell surface and are associated with a collection of coreceptor accessory
and invariant CD3 proteins. In contrast to immunoglobulins, the T-cell
Fabienne McClanahan and John Gribben* receptor is not secreted and also remains membrane bound through-
out the activation process. In the majority of T cells, the T-cell receptor
heterodimer consists of an α and a β chain, but a small subset of T cells
expresses a γδ heterodimer. Following the rule of allelic exclusion, each
SUMMARY individual T cell expresses a single α and a single β chain (or a single
γ or δ chain, respectively), and can either be αβ or γδ. Each chain is com-
All T cells express a receptor for antigen that is formed by two polymorphic posed of a variable region, consisting of a hydrophobic leader sequence
polypeptides that invariably are associated with a collection of invariant of 18 to 29 amino acids and an aminoterminal domain of 102 to 119
proteins, namely CD3γ, CD3δ, CD3ε, and CD247. These invariant proteins amino acids, and a constant region with a carboxyl-terminal region seg-
are necessary for surface expression and signaling by the T-cell receptor. ment of 87 to 113 amino acids. The variable region is responsible for
The two polypeptides that form the T-cell receptor on most T cells are termed the variation in the primary structure among different T-cell receptor
α and β. A small subset of T cells has receptors formed by different polypep- polypeptides and represents the antigen-binding site, while the con-
tides termed γ and δ. The polypeptides of the T-cell receptor have a diversity stant region is invariant among chains of the same class. Similar to other
that is comparable to that estimated for immunoglobulin molecules. However, surface-membrane receptors, each chain is followed by a small connect-
ing peptide, a transmembrane region of 20 to 24 amino acids, and a
unlike immunoglobulins, the T-cell receptors recognize small fragments of small cytoplasmic region of 5 to 12 residues at the carboxyl terminus
antigen only if they are presented to them by defined major histocompatibility anchoring the polypeptide in the cell membrane. The T-cell receptor
complex molecules on the plasma membrane of another cell, the antigen- chains fold into tertiary structures that are very similar to that of the
presenting cell. The response of the T cell to antigen depends on the intensity light and heavy chains of the immunoglobulin molecule. Overall, the
of the signal generated by ligation of the T-cell receptor, and is modified by the structural similarities between the T-cell receptor and immunoglobu-
simultaneous ligation of other accessory molecules. Interactions at the contact lins place the genes encoding these receptor proteins in the so-called
sites between T-cells and antigen-presenting cells are organized in the immu- immunoglobulin supergene family.
nologic synapse. The outcome of T-cell antigen recognition can range from
immune activation and T-cell proliferation to specific T-cell tolerance and/or αβ Heterodimers
programmed cell death. More than 90 percent of mature T cells express an αβ heterodimer, mak-
ing this the major class of T-cell receptor. Without glycan side chains,
each α or β polypeptide has a respective size of only 27 kDa or 32 kDa.
However, within minutes after being translated into protein, both
chains are glycosylated and assembled into a heterodimer composed of
a single acidic α glycoprotein of 39 to 46 kDa linked to a more basic
Acronyms and Abbreviations: AP-1, activation protein-1; APC, antigen-presenting 40- to 44-kDa β-glycoprotein via a disulfide bond between the constant
cell; CTLA-4, cytotoxic T-lymphocyte antigen 4; ERK, extracellular receptor- regions of the two chains (Fig. 76–1).
activated kinase; FOXP3, forkhead box P3; ICAM, intercellular adhesion molecule;
IFN-γ, interferon-gamma; IL, interleukin; IPEX syndrome, immune dysregulation, γδ Heterodimers
polyendocrinopathy, enteropathy, X-linked syndrome; ITAM, immunoreceptor Less than 10 percent of blood T cells and thymocytes exclusively express
tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory a γδ heterodimer. Within the γδ T-cell population, specific γδ T-cell
motif; iT , induced regulatory T cell; JNK, c-Jun N-terminal kinase; LAT, linker of subsets can be defined by their T-cell receptor gene element usage, and
REG
activation of T cells; LFA, lymphocyte function associated; MAP, mitogen-activated their functionally distinct responses to infections with certain organ-
protein; MHC, major histocompatibility complex; NFAT, nuclear factor of activated isms such as Listeria monocytogenes. Alternatively, γδ T cells can be
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T cell; PKC, protein kinase C; PLC-γ , phospholipase C-1 gamma; RORγt, retinoic acid- grouped according to their tissue location. In secondary lymphoid tis-
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related orphan receptor γ thymus isoform; SAPK, stress-activated protein kinase; sues, only 1 to 5 percent of the CD3-positive T cells express γδ recep-
SH2 domain, Src homology 2 domain; SH3 domain, Src homology 3 domain; STAT, tors. Murine studies demonstrate that many epithelial tissues, such as
signal transducer and activator of transcription; T cell, follicular helper T cell; TGF-β, the epidermis, the intestine, the lung, and the uterus, are enriched for
FH
transforming growth factor beta; Th17, CD4+ T-cell subset that produces cytokines γδ-expressing T cells, indicating that γδ T cells are involved in the sur-
of the interleukin-17 family; T , CD4+CD25+ regulatory T cells; V-like, variable- veillance of body barriers. 3
REG
region-like; VLA, very-late activation; ZAP-70, zeta-associated protein of 70 kDa. The amino acid sequence of the γ chain resembles the T-cell recep-
tor β chain, whereas the amino acid sequence of the δ chain resembles
the α chain. Like the homologous αβ heterodimer, the γδ heterodimer is
also associated with the CD3 complex and is capable of initiating T-cell
*This chapter was written by Thomas J. Kipps, M.D., Ph.D. in the 8th edition and activation upon binding of specific ligands. Despite the similarities
portions of that chapter have been retained. in chain structure and size, however, the tertiary structure of variable

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