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.
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.
Lin
T
T
Department of Medicine, University of Wisconsin Hospitals, Madison, USA.
Matsuzaki
G
G
Umesue
M
M
Omoto
K
K
Yoshida
H
H
Harada
M
M
Singaram
C
C
Hiromatsu
K
K
Nomoto
K
K
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D005333:Fetus; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000187:drug effects*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects*; D013950:Thymus Gland / Q000637:transplantation
D007166:Immunosuppressive Agents; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016572:Cyclosporine