Induction of T cell exhaustion by JAK1/3 inhibition in the treatment of alopecia areata

Alopecia areata (AA) is an autoimmune disease caused by T cell-mediated destruction of the hair follicle (HF). Therefore, approaches that effectively disrupt pathogenic T cell responses are predicted to have therapeutic benefits for AA treatment. T cells rely on the duality of T cell receptor (TCR) and gamma chain (gc) cytokine signaling for their development, activation, and peripheral homeostasis. Ifidancitinib is a potent and selective next-generation JAK1-3 inhibitor predicted to disrupt gc cytokine signaling. We found that Ifidancitinib robustly induced hair regrowth in AA-affected C3H/HeJ mice when fed with Ifidancitinib in chow diets. Skin taken from Ifidancitinib-treated mice showed significantly decreased AA-associated inflammation. CD44+CD62L- CD8+ T effector memory cells, which are associated with the pathogenesis of AA, were significantly decreased in the peripheral lymphoid organs in Ifidancitinib-treated mice. We observed high expression of co-inhibitory receptors PD-1 on effector memory CD8+ T cells, together with decreased IFN-g production in Ifidancitinib-treated mice. Furthermore, we found that gc cytokines regulated T cell exhaustion. Taken together, our data indicate that selective induction of T cell exhaustion using a JAK inhibitor may offer a mechanistic explanation for the success of this treatment strategy in the reversal of autoimmune diseases such as AA.

斑秃（Alopecia areata, AA）是一种由T细胞介导破坏毛囊（hair follicle, HF）的自身免疫性疾病。因此，能够有效阻断致病性T细胞应答的策略，有望为AA的治疗带来临床获益。T细胞的发育、活化及外周稳态依赖于T细胞受体（T cell receptor, TCR）与γ链（gamma chain, gc）细胞因子信号通路的协同调控。伊非达替尼（Ifidancitinib）是一种强效且高选择性的新一代JAK1-3抑制剂，可阻断γ链细胞因子信号通路。我们发现，在AA造模的C3H/HeJ小鼠的普通饲料中添加伊非达替尼喂养后，可显著促进受试小鼠的毛发再生。对伊非达替尼处理小鼠的皮肤组织进行检测可见，其AA相关炎症水平显著降低。与AA发病机制密切相关的CD44⁺CD62L⁻ CD8⁺效应记忆T细胞，在伊非达替尼处理小鼠的外周淋巴器官中数量显著减少。我们还观察到，在伊非达替尼处理组小鼠的效应记忆CD8⁺ T细胞表面，共抑制受体程序性死亡受体1（PD-1）呈高表达，同时小鼠体内干扰素γ（IFN-γ）的产生水平显著下调。进一步研究证实，γ链细胞因子可调控T细胞耗竭过程。综上，本研究数据表明，通过JAK抑制剂选择性诱导T细胞耗竭，可为该治疗策略逆转斑秃等自身免疫性疾病的临床疗效提供机制层面的合理解释。