Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells.
Reciprocal differentiation of immunosuppressive CD4(+)CD25(+)FoxP3(+) T regulatory cells (Tregs) and proinflammatory IL-17-producing cells (Th17) from naïve CD4 cells is contingent upon the cytokine environment. Using MACS-purified CD4 cells, we found that rapamycin and cyclosporine A (CsA) potently inhibited the TGFbeta and IL-6-induced generation of IL-17-producing cells. Intriguingly, rapamycin promoted, while CsA markedly inhibited, TGFbeta-mediated generation of Tregs. The aforementioned effects of rapamycin and CsA were also observed for Flow-sorted CD4(+)CD25(-) T cells, indicating that the effect of these two immunosuppressive agents was based on their action on de novo generation of Tregs and Th17 cells from naïve CD4 cells. Our observation suggests a distinct mode of immunosuppressive action and tolerance induction by rapamycin and CsA. The capacity of rapamycin to generate immunosuppressive Tregs and to suppress differentiation of pathogenic Th17 cells furthers our understanding of the basis for the therapeutic immunosuppressive effects of rapamycin in patients with autoimmune diseases and allo-transplantation reactions.
Kopf
Heather
H
Laboratory of Molecular Immunoregulation, Center for Cancer Research, NCI-Frederick, Frederick, Maryland 21702-1201, USA.
de la Rosa
Gonzalo M
GM
Howard
O M Zack
OM
Chen
Xin
X
D000818:Animals; D002454:Cell Differentiation; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020381:Interleukin-17 / Q000096:biosynthesis*; D038041:Lymphopoiesis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D020123:Sirolimus