The kinase ITK controls a Ca(2+)-mediated switch that balances T(H)17 and T(reg) cell differentiation.

The balance of proinflammatory T helper type 17 (T(H)17) and anti-inflammatory T regulatory (T(reg)) cells is crucial for immune homeostasis in health and disease. The differentiation of naïve CD4(+) T cells into T(H)17 and T(reg) cells depends on T cell receptor (TCR) signaling mediated, in part, by interleukin-2-inducible T cell kinase (ITK), which stimulates mitogen-activated protein kinases (MAPKs) and Ca(2+) signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4(+) T cells cultured under T(H)17-inducing conditions expressed the T(reg) transcription factor Foxp3 and did not develop into T(H)17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the T(reg):T(H)17 ratio in the lung. These switched Foxp3(+) T(reg)-like cells had suppressive function, and their transcriptomic profile resembled that of differentiated, induced T(reg) (iT(reg)) cells, but their chromatin accessibility profiles were intermediate between T(H)17 and iT(reg) cells. Like iT(reg) cells, switched Foxp3(+) T(reg)-like cells had reductions in the expression of genes involved in mitochondrial oxidative phosphorylation and glycolysis, in the activation of the mechanistic target of rapamycin (mTOR) signaling pathway, and in the abundance of the T(H)17 pioneer transcription factor BATF. This ITK-dependent switch between T(H)17 and T(reg) cells depended on Ca(2+) signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of T(H)17 and T(reg) cells.