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1176 Part IX: Lymphocytes and Plasma Cells Chapter 76: Functions of T Lymphocytes: T-cell Receptors for Antigen 1177

leukemia (T-ALL), and guide clinical decision making and provide with MHC class I molecules, CD1 molecules present larger extracel-
prognostic information. 6,7 lular peptides in a MHC class II-like fashion, and are also able to pres-
ent glycolipids to T cells. Glycolipids are components of mycobacterial
ANTIGEN PRESENTATION TO T-CELL RECEPTOR membranes; in cells infected with mycobacteria, the CD1 molecules
are therefore able to bind and present membrane components such as
HETERODIMERS lipoarabinomannan or mycolic acid. T cells that recognize these com-
Despite their similarities in structure, there are important differences in plexes play an important role in the immune response to Mycobacterium
the way that T-cell receptors and immunoglobulins recognize antigen: tuberculosis. 14,15
immunoglobulins can bind antigens directly, while T-cell receptors gen- As discussed above, structural studies show that γδ TCRs assume
erally require that peptide antigens are bound to a molecule of the major a different tertiary structure than αβ TCRs. As a consequence, γδ TCRs
8,9
histocompatibility complex (MHC) on the surface of another cell. are able to recognize a wider variety of ligands, such as bacterial phos-
MHC molecules, also known as histocompatibility antigens, are highly phoantigens, nonclassical MHC-I molecules and unprocessed proteins,
16
polymorphic glycoproteins, and have immunoglobulin-like structures which distinguishes them from the great majority of αβ T cells. Other
17
themselves. There are two basic classes of MHC molecules: Class I MHC γδ receptors can recognize determinants presented by CD1 molecules.
molecules generally bind and present intracellular proteins, that is, pep- A number of studies have described increased numbers of γδ T cells in
tides that are derived from proteins synthesized and degraded in the a variety of infectious and autoimmune diseases. Therefore, it is specu-
cytoplasm of the cell. Class II MHC molecules generally bind peptides lated that γδ T cells link innate and adaptive immune responses under
that are derived from exogenous proteins and degraded in intracellular infectious and inflammatory conditions. In addition, it is hypothesized
vesicles. The human histocompatibility antigens HLA-A, HLA-B, and that γδ T cells might play a role in novel T-cell-based immunotherapy
HLA-C are class I molecules, whereas HLA-D antigens DP, DQ, and DR strategies. 18,19
are examples of class II molecules.
MHC class I molecules bind peptides that are usually 8 to 10 amino GENERATION OF T-CELL RECEPTOR DIVERSITY
acids long. Their binding is stabilized by contacts in the free amino and
carboxyl termini of the peptide and the peptide-binding groove of all TCR diversity is achieved by several mechanisms, some of which are
MHC class I molecules. In addition, the peptide-binding groove is the same as those that generate diversity among immunoglobulin mol-
closed at both ends. The corresponding binding groove on class II mol- ecules (Chap. 75). The joining of different V (variable), D (diversity),
ecules is open at either end, and peptides that bind to MHC class II and J (joining) elements to produce a complete V gene, the presence
molecules are generally at least 13 amino acids long. For both class I and of uncorrected errors made during the recombination of these genetic
class II molecules, the peptide binding groove is located in the central elements, and the combinatorial diversity afforded by the random pair-
cleft between the two α helices of the MHC molecule. Steric factors, ing of two chains encoded by separated gene complexes all function
hydrogen bonding, and hydrophobic interactions between the peptide to enhance the diversity of the T-cell antigen receptor repertoire. An
and the MHC molecule stabilize the peptide within this cleft and gener- important difference between T cells and B cells, however, is that B cells
ate a tertiary structure that is further modified by amino acid residues are capable of undergoing somatic hypermutation (Chap. 75). This pro-
of both the MHC and the peptide antigen. cess requires expression of activation-induced deaminase (AID) along
MHC molecules are encoded by a family of MHC genes, which are with other enzymes expressed primarily by B cells within the germinal
located on chromosome 6 in humans (Chap. 137). MHC genes can be center of secondary lymphoid tissue during the immune response to
divided into three subgroups, with antigen presentation being encoded antigen (Chaps. 6 and 75).
by class I (i.e., HLA-A, -B, -C) and class II (i.e., HLA-DP, DQ, DR) genes. TCRs do not undergo somatic mutation, probably because of the
Each of these gene loci exists in different alleles, and both maternal and central role they play in directing host immune defenses: During dif-
paternal alleles are expressed concomitantly. The particular combina- ferentiation, immature αβ T-cell precursors pass through the thymus,
tion of class I and class II MHC alleles found on an individual chro- where they are educated to distinguish self from non-self by cell-surface
mosome is known as the MHC haplotype. Therefore, the number of proteins of the MHC (Chaps. 6 and 74). Because the ligand for the αβ
different MHC molecules is greatly increased not only by MHC gene TCR is processed antigen presented by MHC molecules, close interac-
polymorphism, but also by codominant expression of MHC gene prod- tion with the MHC might be lost if the variable region of the TCR were
ucts. The resulting differences within MHC molecules are primarily allowed to diverge significantly from the inherited germline repertoire.
found in the amino acids lining the clefts that hold the peptide antigen, Furthermore, somatic mutation of expressed TCR variable region genes
allowing the MHC molecules encoded by each allele to bind a distinc- may lead to constitutive T-cell activation to processed self-antigen pre-
tive array of different peptides. sented by self-MHC molecules, which could lead to a breakdown in tol-
Structural studies show that the T-cell receptor can recognize both erance to self-antigens and autoimmunity.
the MHC-bound peptide and the polymorphic amino acid residues
themselves that surround the peptide-binding pocket. The specificity
10
of a T-cell receptor (TCR) is defined both by the peptide it recognizes THE INVARIANT CHAINS OF THE T-CELL
and by the MHC molecule binding it, and TCRs are therefore likely to RECEPTOR COMPLEX
engage a composite peptide/MHC receptor. 11,12 Additional TCR–MHC
binding parameters, such as ligands per cell or dissociation time defined COMPOSITION OF THE T-CELL RECEPTOR
by the affinity of antigen, also have an effect on subsequent T-cell activa-
tion, but their exact relationship remains largely controversial. 13 COMPLEX
Some T cells, however, do not recognize MHC-bound peptides. The CD3 complex of polypeptides and CD247, also known as the zeta
Instead they recognize antigens that are presented by MHC class I-like chain (ζ chain) of the TCR, are closely associated with and required
20
molecules encoded by genes that map outside the MHC region. One for the surface expression of the polypeptide heterodimer. Unlike the
such family of molecules is called CD1. Despite structural similarities TCR heterodimers, these polypeptides are invariant and are found on

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