T cell selection

The ability to trace T cell clones according to their TCR a//3 chain expression has led to the demonstration of MHC-dependent negative and positive selection in the thymus. These studies also provide strong evidence for the involvement of the CDS molecule in class I-mediated positive selection. Although the precise role of CD8 in this process is not known, there is good evidence that the generation of single-

positive CD8 cells from double-positive (CD4+8 + ) precursors in the thymus is associated with class I MHC recognition. Possibly, coordinate ligation of TCR and CD8 with class I MHC at the CD4+8+ precursor stage induces the cell to shut off CD4 expression. Alternatively, CD4 or CD8 might be eliminated on a random basis at the double-positive stage, allowing the formation of single-positive CD8 cells or CD4 cells. The former CD8+4" population would be equipped to be selected by class I MHC, while the latter (CD8"4+) cells would display a TCR specific for class II and would die in the thymus. CD8 may also contribute to negative selection, as highly elevated levels of CD 8 a block thymocyte maturation. Immature CD4+CD8+ thymocytes express CD8 at levels fourfold higher than CD4; nevertheless, activation of p56kk is mostly seen after ligation of CD4 but not CD 8, as a minority of surface CD 8 molecules are associated with p56Ick. It has been shown that negative selection does not require increased CD8-dependent signaling through p56kk. A critical question that remains to be answered involves the role of CD 8 in the differentiation of cytotoxic cells. Possibly, a signal mediated by CD8 results in the differentiation of a thymic precursor cell to a prekiller and killer cell. An alternative explanation is that CD 8 represents part of the mature cytolytic cell program. In either case, a critical feature of CD 8 expression is restriction of cytolytic responses to T cells that recognize class I but not class II MHC products. This feature of the CD8 genetic program may prevent cytolytic cells from reacting to and eliminating class II-bearing B cells and macrophages that display relevant peptide antigens.

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