Fig. 5.4 ). Lymphocytes develop from precursors in the generative (primary) lymphoid organs; T lymphocytes mature in the thymus, whereas B lymphocytes mature in the bone marrow. Each T or B lymphocyte and its progeny, which constitute a clone, express a single antigen receptor, and the total population of lymphocytes (numbering about 1012 in humans) can recognize tens or hundreds of millions of antigens. The enormous diversity of antigen receptors is encoded by variant DNA sequences that are created during lymphocyte maturation by the joining and diversification of different gene segments to form functional antigen receptor genes, a process that occurs only in B cells and T cells. Hence the presence of rearranged antigen receptor genes is a reliable marker of these cells. As already mentioned, the antigen receptors that are expressed in B cells are called antibodies, while their T-cell counterparts are called T-cell receptors.
Mature T and B lymphocytes recirculate through peripheral (secondary) lymphoid organs—the lymph nodes, spleen and mucosal tissues—and reside in these organs and in most tissues. Foreign antigens are concentrated in these organs, where they bind to and activate the clones of lymphocytes that express receptors for those antigens, a process known as clonal selection. All mature lymphocytes go through distinct phases during their lives— naïve lymphocytes express antigen receptors but have not responded to antigens and do not serve any functions; effector lymphocytes are induced by lymphocyte activation and perform the functions that eliminate microbes; and memory lymphocytes, induced during activation, survive in a functionally silent state even after the antigen is eliminated and respond rapidly upon subsequent encounters with the antigen.
Thymus-derived T lymphocytes develop into the effector cells of cellular immunity and “help” B cells to produce antibodies against protein antigens. T cells constitute 60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones. T cells cannot recognize free or circulating antigens; instead, the vast majority (>95%) of T cells sense only peptide fragments of proteins displayed by molecules of the major histocompatibility complex (MHC), discussed in more detail later. Because T cell antigen receptors have evolved to see MHC-bound peptides on cell surfaces, T cells only recognize antigens presented by other cells. The outcome of this interaction varies dramatically depending on the type of T cell that is involved and the identity of the other interacting cell, ranging from the killing of virus-infected cells to the activation of phagocytes or B lymphocytes that have ingested protein antigens.
Peptide antigens presented by MHC molecules are recognized by the T-cell receptor (TCR), a heterodimer that in most T cells is composed of disulfide-linked α and β protein chains (
Fig. 5.5). Each chain has a variable region that participates in binding a particular peptide antigen and a constant region that interacts with associated signaling molecules. TCRs are noncovalently linked to a cluster of five invariant polypeptide chains, the γ, δ, and ε proteins of the CD3 molecular complex and two ζ chains (see
Fig.
5.5 ). The CD3 proteins and ζ chains do not bind antigens; instead, they are attached to the TCR and initiate intracellular biochemical signals after TCR recognition of antigen.