AN OPPOSITE PATTERN OF SELECTION OF A SINGLE T-CELL ANTIGEN RECEPTOR IN THE THYMUS AND AMONG INTRAEPITHELIAL LYMPHOCYTES

The differentiation of intestinal intraepithelial lymphocytes (IEL) re mains controversial, which may be due in part to the phenotypic comple xity of these: T cells. We have investigated hers the development of I EL in mice on the recombination activating gene (RAG)-2(-/-) backgroun d which express a T cell antigen receptor (TCR) transgene specific for an H-Y peptide presented by D-b (H-Y/D-b X RAG-2(-) mice). In contras t to the thymus, the small intestine in female H-Y/D-b X RAG-2(-) mice is severely deficient in the number of IEL; TCR transgene(+) CD8 alph a alpha and CD8 alpha beta are virtually absent. This is similar to th e number and phenotype of IEL in transgenic mice that do not express t he D-b class I molecule, and which therefore fail positive selection. Paradoxically, in male mice, the small intestine contains large number s of TCR+ IEL that express high levels of CD8 alpha alpha homodimers. The IEL isolated from male mice are functional, as they respond upon T CR cross-linking, although they are not autoreactive to stimulator cel ls from male mice. We hypothesize that the H-Y/Db TCR fails to undergo selection in IEL of female mice due to the reduced avidity of the TCR for major histocompatibility complex peptide in conjunction with the CD8 alpha alpha homodimers expressed by many cells in this lineage. By contrast, this reduced TCR/CD8 alpha alpha avidity may permit positiv e rather than negative selection of this TCR in male mice. Therefore, the data presented provide conclusive evidence that a TCR which is pos itively selected in the thymus will not necessarily be selected in IEL , and furthermore, that the expression of a distinct CD8 isoform by IE L may be a critical determinant of the differential pattern of selecti on of these T cells.