The kinase ITK controls a Ca-mediated switch that balances T17 and T cell differentiation.

The balance of proinflammatory T helper type 17 (T17) and anti-inflammatory T regulatory (T) cells is crucial for immune homeostasis in health and disease. The differentiation of naïve CD4 T cells into T17 and T 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 signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4 T cells cultured under T17-inducing conditions expressed the T transcription factor Foxp3 and did not develop into T17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the T:T17 ratio in the lung. These switched Foxp3 T-like cells had suppressive function, and their transcriptomic profile resembled that of differentiated, induced T (iT) cells, but their chromatin accessibility profiles were intermediate between T17 and iT cells. Like iT cells, switched Foxp3 T-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 T17 pioneer transcription factor BATF. This ITK-dependent switch between T17 and T cells depended on Ca signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of T17 and T cells.