Development of TCR-gamma delta CD4-CD8+ alpha alpha but not TCR-alpha beta CD4-CD8+ alpha alpha i-IEL is resistant to cyclosporin A.

Abstract

Present evidence suggests that cyclosporin A (CSA) inhibits the development of both alpha beta and gamma delta T cells in the thymus. However, whether CSA can inhibit the development of murine intestinal intraepithelial lymphocytes (i-IEL) is unknown as most i-IEL are clearly derived from a different lineage than the conventional thymus-derived T cells found in the periphery. Using the adult thymectomized, lethally irradiated bone-marrow reconstituted chimera (ATXBM mice) as a model for the development of extrathymically derived i-IEL and the fetal thymus-grafted (FTG) nude mice as a model for the development of thymically derived i-IEL, we demonstrate that CSA nearly completely inhibited the 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 different from those in control mice, and the TCR-gamma delta i-IEL in CSA-treated mice appear to be mature and activated as most were large, granular, 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 activation cascade involved after TCR stimulation between TCR-alpha beta CD4-CD8+ alpha alpha and TCR-gamma delta CD4-CD8+ alpha alpha i-IEL are markedly different.