Research ArticleImmunology

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

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Science Signaling  08 Dec 2020:
Vol. 13, Issue 661, eabb0619
DOI: 10.1126/scisignal.abb0619

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Tripping the regulatory switch

Given the important role that regulatory T (Treg) cells play in preventing autoimmunity by suppressing the deleterious effects of effector T (Teff) cells, strategies that increase Treg cell numbers in vivo are of great interest. Mendu et al. found that loss of the channel and kinase TRPM7 in T cells led to an increase in Treg cell number in mice and protected against Teff cell–dependent hepatitis. Loss or inhibition of TRPM7 in T cells increased their sensitivity to the cytokine interleukin-2 (IL-2), enhanced signaling downstream of the IL-2 receptor, and increased expression of transcriptional regulator FOXP3, thereby promoting Treg cell development in the thymus. These results suggest that targeting TRPM7 may provide a strategy to increase Treg cell numbers in vivo.

Abstract

The thymic development of regulatory T (Treg) cells, crucial suppressors of the responses of effector T (Teff) cells, is governed by the transcription factor FOXP3. Despite the clinical importance of Treg 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 Treg cells in mice and led to a substantially higher frequency of functional Treg 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 α-subunit and activation of the transcriptional regulator STAT5. Enhanced IL-2 signaling increased the expression of Foxp3 in thymocytes and promoted thymic Treg (tTreg) cell development. Thus, these data indicate that inhibiting TRPM7 activity increases Treg cell numbers, suggesting that it may be a therapeutic target to promote immune tolerance.

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