Effects of cyclosporine A on T cell development and clonal deletion.
Cyclosporine A (CsA) is an important immunosuppressive drug that is widely used in transplantation medicine. Many of its suppressive effects on T cells appear to be related to the inhibition of T cell receptor (TCR)-mediated activation events. Paradoxically, in certain situations CsA is responsible for the induction of a T cell-mediated autoimmunity. The effects of CsA on T cell development in the thymus were investigated to elucidate the physiologic events underlying this phenomenon. Two major effects were revealed: (i) CsA inhibits the development of mature single positive (CD4+8- or CD4-8+) TCR-alpha beta+ thymocytes without discernibly affecting CD4-8- TCR-gamma delta+ thymocytes and (ii) CsA interferes with the deletion of cells bearing self-reactive TCRs in the population of single positive thymocytes that do develop. This suggests a direct mechanism for CsA-induced autoimmunity and may have implications for the relative contribution of TCR-mediated signaling events in the development of the various T cell lineages.
Jenkins
M K
MK
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Schwartz
R H
RH
Pardoll
D M
DM
D000818:Animals; D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D001327:Autoimmune Diseases / Q000139:chemically induced; D002454:Cell Differentiation / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D003524:Cyclosporins; D011948:Receptors, Antigen, T-Cell