Peripherally induced Tregs (iTregs) are being recognized as a functional and physiologically relevant T-cell subset. Understanding the molecular basis of their development is a necessary step before the therapeutic potential of iTreg manipulation can be exploited. In this study, we report that the differentiation of primary human T cells to suppressor iTregs involves the relocation of key proximal TCR signaling elements to the highly active IL-2-Receptor (IL-2-R) pathway. In addition to the recruitment of lymphocyte-specific protein tyrosine kinase (Lck) to the IL-2-R complex, we identified the dissociation of the voltage-gated K(+) channel Kv1.3 from the TCR pathway and its functional coupling to the IL-2-R. The regulatory switch of Kv1.3 activity in iTregs may constitute an important contributing factor in the signaling rewiring associated with the development of peripheral human iTregs and sheds new light upon the reciprocal crosstalk between the TCR and the IL-2-R pathways.
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