Cutting Edge: Foxp3-Mediated Induction of Pim 2 Allows Human T Regulatory Cells to Preferentially Expand in Rapamycin

Abstract

Addition of rapamycin to cultures of expanding natural CD4+CD25+Foxp3+ T regulatory cells (Tregs) helps maintain their suppressive activity, but the underlying mechanism is unclear. Pim 2 is a serine/threonine kinase that can confer rapamycin resistance. Unexpectedly, pim 2 was found to be constitutively expressed in freshly isolated, resting Tregs, but not in CD4+CD25− T effector cells. Introduction of Foxp3, but not Foxp3Δ2, into effector T cells induced pim 2 expression and conferred preferential expansion in the presence of rapamycin, indicating that Foxp3 can regulate pim 2 expression. Finally, we determined there is a positive correlation between Treg expansion and Foxp3 expression in the presence of rapamycin. Together, these results indicate that Tregs are programmed to be resistant to rapamycin, providing further rationale for why this immunosuppressive drug should be used in conjunction with expanded Tregs.

Pretreatment of Rapamycin Before Allogenic Corneal Transplant Promotes Graft Survival Through Increasing CD4+CD25+Foxp3+ Regulatory T Cells

“…[22][23] Moreover, Foxp3 expression induced pim2 expression in Tregs, which allowed for a selective growth advantage of Treg in the presence of rapamycin. 24 It is noteworthy that the elevated expression of CD4 + CD25 + Foxp3 + Treg induced by preoperative treatment of rapamycin sustained at least 2 weeks in peripheral blood, draining lymph nodes, and corneal tissue even after the withdrawal of rapamycin, as shown in the present study. It has been reported that in vivo rapamycin administration contributed to selective activation and expansion of CD4 + CD25 + Foxp3 + Treg, not only in peripheral blood, but also, in secondary lymphoid organs and grafts, both of which merit graft survival.…”

Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8+T-cell proliferation and survival

“…[14][15][16] In fact, in the tumor microenvironment, mTOR inhibition leads to a decrease in the proliferation of CD8 C T cells by direct inhibition coupled with a significant increase in the suppressive regulatory T-cell (Treg) population. 17 Rapamycin has been shown to support the proliferation and survival of Treg cells [18][19][20][21] due to a feedback loop where mTOR inhibition results in PI3K-dependent Akt activation, which sustains signaling through mTOR. 22 Accordingly, antibody-based depletion of Treg cells was proposed recently as a strategy to counteract this inhibition of CD8 C T cells when rapamycin is used to augment memory T cells.…”

Inhibition of Pim2-prolonged skin allograft survival through the apoptosis regulation pathway

“…1 CD25 1 T cells 14 with a twofold higher expression of pim2 than in CD4 1 CD25 2 T-cells, 6 whereas other reports have not found any differences between these two subsets. 24,25 However, all of the data shown in our experiments demonstrated that pim2 facilitates the allograft rejection, suggesting that this gene may be expressed in effector CD4 1 CD25 2 T cells.…”