variable (see Section 5-8). But among this variability, certain amino acids are conserved and common to many V segments. Analysis of numerous crystal structures has revealed that when the T-cell receptor binds a peptide:MHC complex, specific amino acids of the Vβ region interact with a particular part of the MHC protein. For example, in many human and mouse Vβ regions, the CDR2 has a tyrosine at position 48, and this interacts with a region in the middle of the α1 helix of MHC class I and class II proteins. Two other amino acids commonly found in other Vβ regions (tyrosine at 46 and glutamic acid at 54) interact with the same region of MHC. T cells expressing Vβ genes with mutations at any of these positions showed reduced positive selection, demonstrating that the interaction of such V regions with MHC molecules contributes to T-cell development.
8-21 Positive selection coordinates the expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the T cell.
At the time of positive selection, the thymocyte expresses both CD4 and CD8 co-receptor molecules. By the end of thymic selection, mature α:β T cells ready for export to the periphery have stopped expressing one of these co-receptors. The majority of these cells belong to the conventional CD4 or CD8 T-cell lineages. Less abundant subsets, such as iNKT cells and a subset of regulatory T cells expressing CD4 and high levels of CD25, also develop in the thymus from CD4+CD8+ cells. Moreover, almost all mature T cells that express CD4 have receptors that recognize peptides bound to self MHC class II molecules and are programmed to become cytokine-secreting helper T cells. In contrast, most of the cells that express CD8 have receptors that recognize peptides bound to self MHC class I molecules and are programmed to become cytotoxic effector cells. Thus, positive selection also determines the cell-surface phenotype and functional potential of the mature T cell, selecting the appropriate co-receptor for efficient antigen recognition and the appropriate program for the T cell’s eventual functional differentiation in an immune response.
Experiments with mice transgenic for rearranged T-cell receptor genes show clearly that the specificity of the T-cell receptor for self peptide:self MHC complexes determines which co-receptor a mature T cell will express. If the transgenes encode a T-cell receptor specific for antigen presented by self MHC class I molecules, mature T cells that express the transgenic receptor are CD8 T cells. Similarly, in mice made transgenic for a receptor that recognizes antigen with self MHC class II molecules, mature T cells that express the transgenic receptor are CD4 T cells (Fig. 8.27).
The importance of MHC molecules in this selection is illustrated by the human immunodeficiency diseases caused by mutations that lead to an absence of MHC molecules on lymphocytes and thymic epithelial cells. People who lack MHC class II molecules have CD8 T cells but only a few, highly abnormal CD4 T cells; a similar result has been obtained in mice in which MHC class II expression has been eliminated by targeted gene disruption (see Appendix I, Section A-35). Likewise, mice and humans that lack MHC class I molecules lack CD8 T cells. Thus, MHC class II molecules are absolutely required for CD4 T-cell development, whereas MHC class I molecules are similarly required for CD8 T-cell development.