Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells

Abstract

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 TGFβ and IL-6-induced generation of IL-17-producing cells. Intriguingly, rapamycin promoted, while CsA markedly inhibited, TGFβ-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.

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

“…In vitro studies suggest that rapamycin reduces Th17 polarization through direct T‐cell effects (Kopf et al ., 2007) contrasting with our in vivo data (Fig. 3).…”

Retracted: CCR5 blockade in combination with rapamycin prolongs cardiac allograft survival in mice

“…+ Tregs in vitro and in vivo [30][31][32]. Surviving allografts treated with CCR5 blockade plus rapa were infiltrated with a significant number of CD4 Anti-CCR5 antibody + rapa (n = 5)…”

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

“…Time to platelet engraftment was also similar in the SIR/TAC (median 12 days; range, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and MTX/TAC (median 16 days; range, 10-33) groups (P=0.6). No significant differences were observed in donor chimerism at any of the time points studied (days 30, 90, and 360 post-HCT).…”

“…Time to neutrophil engraftment did not differ between patients treated with SIR/TAC (median 16 days; range, [11][12][13][14][15][16][17][18][19][20][21][22] or MTX/TAC (median 16 days; range, 12-28) (P=0.57). Time to platelet engraftment was also similar in the SIR/TAC (median 12 days; range, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and MTX/TAC (median 16 days; range, 10-33) groups (P=0.6).…”

“…17 SIR also inhibits the differentiation of naïve CD4 T cells into Th17 cells and promotes the generation of Treg. 18 We hypothesized that SIR-based immune suppression would suppress alloreactive T cells, support selective recovery of Treg, and thus prevent GVHD more effectively.…”