Rapamycin Promotes Expansion of Functional CD4+CD25+FOXP3+ Regulatory T Cells of Both Healthy Subjects and Type 1 Diabetic Patients

Abstract

CD4+CD25+FOXP3+ T regulatory cells (Tregs) are pivotal for the induction and maintenance of peripheral tolerance in both mice and humans. Rapamycin has been shown to promote tolerance in experimental models and to favor CD4+CD25+ Treg-dependent suppression. We recently reported that rapamycin allows in vitro expansion of murine CD4+CD25+FoxP3+ Tregs, which preserve their suppressive function. In the current study, we show that activation of human CD4+ T cells from healthy subjects in the presence of rapamycin leads to growth of CD4+CD25+FOXP3+ Tregs and to selective depletion of CD4+CD25− T effector cells, which are highly sensitive to the antiproliferative effect of the compound. The rapamycin-expanded Tregs suppress proliferation of both syngeneic and allogeneic CD4+ and CD8+ T cells. Interestingly, rapamycin promotes expansion of functional CD4+CD25+FOXP3+ Tregs also in type 1 diabetic patients, in whom a defect in freshly isolated CD4+CD25+ Tregs has been reported. The capacity of rapamycin to allow growth of functional CD4+CD25+FOXP3+ Tregs, but also to deplete T effector cells, can be exploited for the design of novel and safe in vitro protocols for cellular immunotherapy in T cell-mediated diseases.

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

“…RAPA, an mTOR kinase inhibitor, is an immunosuppressive drug that inhibits effector T-cell proliferation, migration and cytokine production, 39 and can selectively promote the expansion of suppressive human CD4 1 CD25 hi Foxp3 1 T cells isolated from healthy donors and patients with diabetes. 40,41 It remains unclear whether RAPA selectively suppresses the expansion of non-Treg cells, thereby indirectly promoting the expansion of Foxp3 1 Treg cells. 16 Although a comparison study has shown that both RAPA and atRA had similar effects on promoting and stabilizing Treg cells during their expansion, 42 a more recent study demonstrated that atRA exhibits superior efficacy relative to RAPA for stabilizing nTreg cells under inflammatory conditions.…”

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

“…It is increasingly evident that promotion of Treg activity contributes to the tolerance induced by this compound. For example, Battaglia and colleagues reported that rapamycin selectively expands naturally occurring murine Tregs in vitro (12). Furthermore, Battaglia and Strauss reported rapamycin also selectively promotes expansion of functional human Tregs, while depleting human CD4+CD25− T effector cells (13,14).…”

Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection

“…Under all normally activating conditions, T cells lacking mTORC1 differentiate into Foxp3 + regulatory cells, and this differentiation is associated with hyperactive small mothers against decapentaplegic homolog 3 (Smad3) activation in the absence of exogenous TGF-b [55]. Rapamycin treatment enhances T reg generation [56,57]. However, in natural T regs , mTORC1 is important for their proliferation and function.…”