Targeting the ion channel TRPM7 promotes the thymic development of regulatory T cells by promoting IL-2 signaling

The thymic development of regulatory T (T-reg) cells, crucial suppressors of the responses of effector T (T-eff) cells, is governed by the transcription factor FOXP3. Despite the clinical importance of T-reg cells, there is a dearth of druggable molecular targets capable of increasing their numbers in vivo. We found that inhibiting the function of the TRPM7 chanzyme (ion channel and enzyme) potentiated the thymic development of T-reg cells in mice and led to a substantially higher frequency of functional T-reg cells in the periphery. In addition, TRPM7-deficient mice were resistant to T cell-driven hepatitis. Deletion of Trpm7 and inhibition of TRPM7 channel activity by the FDA-approved drug FTY720 increased the sensitivity of T cells to the cytokine interleukin-2 (IL-2) through a positive feed-forward loop involving increased expression of the IL-2 receptor alpha-subunit and activation of the transcriptional regulator STAT5. Enhanced IL-2 signaling increased the expression of Foxp3 in thymocytes and promoted thymic T-reg (tT(reg)) cell development. Thus, these data indicate that inhibiting TRPM7 activity increases T-reg cell numbers, suggesting that it may be a therapeutic target to promote immune tolerance.