SELECTION OF PERIPHERAL AND INTESTINAL T-LYMPHOCYTES LACKING CD3-ZETA

The CD3 zeta chain of the TCR plays a pivotal role in the activation of T cell responses toward foreign antigen and in the selection of the T cell repertoire. T lymphocytes from mice deficient in CD3 zeta (CD3 zeta/eta(-/-) mice) express very few cell surface TCR-CD3 complexes, and these animals have poorly developed thymuses which lack single-positive CD8 and CD4 thymocytes. Nevertheless, a substantial number of single-positive CD4(+) and CD8(+) T lymphocytes are found in peripheral lymphoid organs of CD3 zeta/eta(-/-) animals. Using double-mutant mice, generated by breeding CD3 zeta/eta(-/-) mice with others deficient in the expression of either class I or class II MHC molecules, we demonstrate here that positive selection of peripheral CD4(+) and CD8(+) T lymphocytes can occur in the absence of CD3 zeta/eta molecules. Analysis of the intestinal intra-epithelial lymphocytes from CD3 zeta/eta(-/-) mice revealed a novel T cell population expressing high levels of an alternative TCR alpha beta, due to the replacement of CD3 zeta by Fc epsilon Rl gamma. Developmentally, these cells also depend on class I MHC expression, In contrast, TCR gamma delta/Fc epsilon Rl gamma(+) T cells develop independently of MHC class I or class II molecules. These experiments demonstrate that the unique subset of intestinal TCR alpha beta/Fc epsilon Rl gamma(+) lymphocytes is developmentally dependent on MHC expression. The restricted expression of TCR alpha beta/Fc epsilon Rl gamma(+) cells in the intestinal mucosa (rather than the thymus or lymph nodes) supports the hypothesis that selection of these T cells occurs extrathymically.