Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells

Abstract

The immunosuppressive drugs rapamycin and cyclosporin A (CsA) are widely used to prevent allograft rejection. Moreover, they were shown to be instrumental in experimental models of tolerance induction. However, it remains to be elucidated whether these drugs have an effect on the CD4 ؉ CD25 ؉ regulatory T-cell (T REG ) population, which plays an important role in allograft tolerance. Recently, we reported that alloantigen-driven expansion of human CD4 ؉ CD25 ؉ T REG s gives rise to a distinct highly suppressive CD27 ؉ T REG subset next to a moderately suppressive CD27 ؊ T REG subset. In the current study we found that rapamycin and CsA do not interfere with the suppressive activity of human naturally occurring CD4 ؉ CD25 ؉ T cells. However, in contrast to CsA, rapamycin preserved the dominance of the potent CD27 ؉ T REG subset over the CD27 ؊ T REG subset after alloantigen-driven expansion of CD4 ؉ CD25 ؉ T REG s in vitro. Accordingly, CD4 ؉ CD25 ؉ T REG s cultured in the presence of rapamycin displayed much stronger suppressive capacity than

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

“…Whether CLL cells can actively induce T regs or whether disease progression in CLL is only a consequence of the given immunologic constitution of a patient cannot be answered by our study. With T regdepleting and T reg -increasing substances in hand, [28][29][30][31] we have the means to test this hypothesis in preclinical tumor models, such as the Tcl1-mouse model for CLL. 32,33 …”

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

“…To do this, we transduced primary human CD4 T cells with a lentiviral vector expressing pim 2 and noted that pim 2 promoted the expansion of CD4 T cells in the presence and absence of rapamycin (data not shown), making it an attractive target to study in Tregs. Studies have shown that the addition of rapamycin at the initiation of a Treg culture preserves the suppressive function of the expanded cells (3,5,8). This suggests that if pim 2 confers rapamycin resistance in Tregs, it should be expressed in resting Tregs.…”

T cell dependence on mTOR signaling

“…These reports dovetail with the clinical observation that immunosuppressed patients treated with rapamycin have increased frequencies of Tregs. 15,16 Intra-epithelial γδ T cells have been described as a distinct subset of T cells with innate properties that bridge the adaptive and innate immune responses. One such population of intra-epithelial γδ T cells resides in the murine skin.…”