Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
Sci Signal. 2024 Jul 23;17(846):eadh2381. doi: 10.1126/scisignal.adh2381.
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.
促炎性辅助性 T 细胞 17（T17）和抗炎性调节性 T（T）细胞之间的平衡对于健康和疾病中的免疫稳态至关重要。幼稚 CD4 T 细胞向 T17 和 T 细胞的分化取决于 T 细胞受体（TCR）信号转导，部分由白细胞介素-2 诱导的 T 细胞激酶（ITK）介导，该激酶刺激有丝分裂原激活的蛋白激酶（MAPKs）和 Ca 信号。在这里，我们报告说，在缺乏 ITK 活性的情况下，在 T17 诱导条件下培养的幼稚鼠 CD4 T 细胞表达 T 转录因子 Foxp3，并且不会发育成 T17 细胞。此外，在过敏炎症期间体内抑制 ITK 活性会增加肺部的 T:T17 比值。这些转换的 Foxp3 T 样细胞具有抑制功能，其转录组谱与分化诱导的 T（iT）细胞相似，但它们的染色质可及性谱介于 T17 和 iT 细胞之间。与 iT 细胞一样，转换的 Foxp3 T 样细胞的基因表达减少，这些基因涉及线粒体氧化磷酸化和糖酵解、机械靶蛋白（mTOR）信号通路的激活以及 T17 先驱转录因子 BATF。这种 ITK 依赖性 T17 和 T 细胞之间的转换取决于 Ca 信号而不是 MAPKs。这些发现表明，通过 ITK 微调 TCR 信号强度以控制 T17 和 T 细胞之间的平衡具有潜在的策略。
