The kinase ITK controls a Ca2+-mediated switch that balances TH17 and Treg cell differentiation

Abstract

The balance of proinflammatory T helper type 17 (T_H17) 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_H17 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 Ca²⁺ signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4⁺ T cells cultured under T_H17-inducing conditions expressed the T_reg transcription factor Foxp3 and did not develop into T_H17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the T_reg:T_H17 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_H17 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_H17 pioneer transcription factor BATF. This ITK-dependent switch between T_H17 and T_reg cells depended on Ca²⁺ signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of T_H17 and T_reg cells.