Targeting ion channel TRPM7 promotes the thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation

Mendu, S. K.; Schappe, M. S.; Moser, E. K.; Krupa, J. K.; Rogers, J. S.; Stipes, E. J.; Parker, C. A.; Braciale, T. J.; Desai, B. N.

doi:10.1101/330233

bioRxiv · 10.1101/330233

Targeting ion channel TRPM7 promotes the thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation

Mendu, S. K.·Schappe, M. S.·Moser, E. K.·Krupa, J. K.·Rogers, J. S.·Stipes, E. J.·Parker, C. A.·Braciale, T. J.·Desai, B. N.

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Abstract

In BriefGenetic deletion of Trpm7 in T-cells or pharmacological inhibition of TRPM7 channel promotes the development of fully functional Treg cells by increasing IL-2R and STAT5-dependent FOXP3 expression in the developing thymocytes. The study identifies the ion channel TRPM7 as a putative drug target to increase Treg numbers in vivo and induce immunotolerance.\n\nHIGHLIGHTSO_LIIon channel TRPM7 controls Treg development\nC_LIO_LIThe deletion of Trpm7 in the T-cell lineage increases fully functional Treg cells in the periphery\nC_LIO_LITRPM7 negatively regulates Foxp3 expression by restraining IL-2-dependent STAT5 activation\nC_LIO_LIInhibition of TRPM7 channel by FTY720 promotes the development of functional Treg cells\nC_LI\n\nSUMMARYThe thymic development of regulatory T cells (Treg), the crucial suppressors of the effector T cells (Teff), is governed by the transcription factor FOXP3. Despite the clinical significance of Treg cells, there is a dearth of druggable molecular targets capable of increasing Treg numbers in vivo. We report a surprising discovery that TRPM7 restrains Treg development by negatively regulating STAT5-dependent Foxp3 expression. The deletion of Trpm7 potentiates the thymic development of Treg cells, leads to a significantly higher frequency of functional Treg cells in the periphery and renders the mice highly resistant to T cell-dependent hepatitis. The deletion of Trpm7 or the inhibition of TRPM7 channel activity by the FDA-approved prodrug FTY720, increases IL-2 sensitivity through a feed forward positive feedback loop involving high IL-2R expression and STAT5 activation. Enhanced IL-2 signaling increases the expression of Foxp3 in thymocytes and promotes the development of Treg cells. Thus, TRPM7 emerges as the first ion channel that can be drugged to increase Treg numbers, revealing a novel pharmacological path toward the induction of immune tolerance.

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Mendu, S. K., Schappe, M. S., Moser, E. K., Krupa, J. K., Rogers, J. S., Stipes, E. J., Parker, C. A., Braciale, T. J., Desai, B. N.. 2018-05-25. Targeting ion channel TRPM7 promotes the thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation. https://doi.org/10.1101/330233

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