The antigen receptor of MHC-restricted CD4+ and CD8+ T lymphocytes is a heterodimer composed of a and P chains (see Chapter 7). There is a second type of clonally distributed receptor composed of heterodimers of y and 8 chains, which are homologous to the a and P chains of the TCRs found on CD4+ and CD8+ T lymphocytes. T cells expressing the y8 TCR represent a lineage distinct from the more numerous aP-expressing T cells. The percentages of y8 T cells vary widely in different tissues and species, but overall, less than 5% of all T cells express this form of TCR. The y8 heterodimer associates with the CD3 and Z proteins in the same way as TCR aP heterodimers do, and TCR-induced signaling events typical of aP-expressing T cells are also observed in y8 T cells. Although the theoretical potential diversity of the y8 TCR is even greater than the diversity of the aP TCR, in reality, only a limited number of y and 8 V regions are expressed in some subsets of these cells, and there is little or no junc-tional diversity.
Different populations of y8 T cells may develop at distinct times during ontogeny, contain different V regions, reside in different tissues, and have a limited capacity to recirculate among these tissues. In mice, many skin y8 T cells develop in neonatal life and express one particular TCR with essentially no variability in the V region, whereas many of the y8 T cells in the vagina, uterus, and tongue appear later and express another TCR with a different V region. The limited diversity of the y8 TCRs in many tissues suggests that the ligands for these receptors may be invariant and conserved. One intriguing feature of y8 T cells is their abundance in epithelial tissues of certain species. For example, more than 50% of lymphocytes in the small bowel mucosa of mice and chickens, called intraepithelial lymphocytes, are y8 T cells. In mouse skin, most of the intraepidermal T cells express the y8 receptor. Equivalent cell populations are not as abundant in humans; only about 10% of human intestinal intraepithelial T cells express the y8 TCR. y8 T cells in lymphoid organs express more diverse TCRs than the epithelial y8 cells.
y8 T cells do not recognize MHC-associated peptide antigens and are not MHC restricted. Some y8 T cell clones recognize small phosphorylated molecules, alkyl amines, or lipids that are commonly found in mycobac-teria and other microbes and that may be presented by "non-classical" class I MHC-like molecules. Other y8 T cells recognize protein or nonprotein antigens that do not require processing or any particular type of APCs for their presentation. Many y8 T cells are triggered by microbial heat shock proteins. A working hypothesis for the specificity of y8 T cells is that they may recognize antigens that are frequently encountered at epithelial boundaries between the host and the external environment.
A number of biologic activities have been ascribed to y8 T cells, including secretion of cytokines and killing of infected cells, but the function of these cells remains poorly understood. It has been postulated that this subset of T cells may initiate immune responses to microbes at epithelia, before the recruitment and activation of antigen-specific aP T cells. However, mice lacking y8 T cells, created by targeted disruption of the y or 8 TCR gene, have little or no immunodeficiency and only a modest increase in susceptibility to infections by some intracellular bacteria.
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