DEVELOPMENT OF TCR-GAMMA-DELTA CD4(-)CD8(-ALPHA BUT NOT TCR-ALPHA-BETA CD4(-)CD8(+)ALPHA-ALPHA I-IEL IS RESISTANT TO CYCLOSPORINE-A()ALPHA)

Present evidence suggests that cyclosporin A (CSA) inhibits the develo pment of both alpha beta and gamma delta T cells in the thymus. Howeve r, whether CSA can inhibit the development of murine intestinal intrae pithelial lymphocytes (i-IEL) is unknown as most i-IEL are clearly der ived from a different lineage than the conventional thymus-derived T c ells found in the periphery. Using the adult thymectomized, lethally i rradiated bone-marrow reconstituted chimera (ATXBM mice) as a model fo r the development of extrathymically derived i-IEL and the fetal thymu s-grafted (FTG) nude mice as a model for the development of thymically derived i-IEL, we demonstrate that CSA nearly completely inhibited th e development of extrathymically, and possibly thymically, derived TCR -alpha beta i-IEL. Most of the TCR-alpha beta i-IEL whose development was inhibited by CSA belonged to the CD4(-)CD8(+) alpha alpha subset. In contrast, the development of extrathymically and thymically derived TCR-gamma delta i-IEL was completely resistant to CSA. The phenotype of CSA-resistant TCR-gamma delta i-IEL in these models was not differe nt from those in control mice, and the TCR-gamma delta i-IEL in CSA-tr eated mice appear to be mature and activated as most were large, granu lar, and CD69(+). Lastly, we demonstrate that CSA does not affect the extrathymic positive selection of V delta 4 i-IEL in C3H hosts. These results suggest that despite their similarity, the intracellular activ ation cascade involved after TCR stimulation between TCR-alpha beta CD 4(-)CD8(+) alpha alpha and TCR-gamma delta CD4(-)CD8(+)alpha alpha i-I EL are markedly different.