Induction of T cell exhaustion by JAK1/3 inhibition in the treatment of alopecia areata.
Induction of T cell exhaustion by JAK1/3 inhibition in the treatment of alopecia areata.
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DOI：
10.3389/fimmu.2022.955038
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
斑秃（AA）是一种由T细胞介导的毛囊破坏（HF）引起的自身免疫性疾病。因此，预测有效破坏致病性T细胞反应的方法对AA治疗具有治疗益处。T细胞依赖于T细胞受体（TCR）和γ链（γc）细胞因子信号的双重性来实现其发育、激活和外周稳态。Ifidancitinib是一种有效的选择性下一代JAK1/3抑制剂，预计会破坏γ - c细胞因子信号传导。我们发现，当在饲料中饲喂伊非丹替尼时，伊非丹替尼能强烈地诱导aa影响的C3H/HeJ小鼠的毛发再生。伊非丹昔替尼处理小鼠的皮肤显示aa相关炎症明显减少。与AA发病机制相关的CD44+CD62L- CD8+ T效应细胞/记忆细胞在非非丹替尼治疗小鼠外周淋巴器官中显著减少。我们观察到共抑制受体PD-1在效应/记忆CD8+ T细胞上的高表达，同时在非非替尼处理的小鼠中IFN-γ的产生减少。此外，我们发现γ - c细胞因子调节T细胞衰竭。综上所述，我们的数据表明，使用JAK抑制剂选择性诱导T细胞衰竭可能为这种治疗策略在逆转自身免疫性疾病（如AA）方面的成功提供了机制解释。
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 benefit for AA treatment. T cells rely on the duality of T cell receptor (TCR) and gamma chain (γc) cytokine signaling for their development, activation, and peripheral homeostasis. Ifidancitinib is a potent and selective next-generation JAK1/3 inhibitor predicted to disrupt γc 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-γ production in Ifidancitinib-treated mice. Furthermore, we found that γc 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.
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影响因子：
64.8
作者：
McKinney EF;Lee JC;Jayne DR;Lyons PA;Smith KG
通讯作者：
Smith KG
影响因子：
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Zerwes, Hans-Guenter
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64.8
作者：
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Wherry, E. John
影响因子：
13.8
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Damsky W;King BA
通讯作者：
King BA
影响因子：
64.8
作者：
La Manno G;Soldatov R;Zeisel A;Braun E;Hochgerner H;Petukhov V;Lidschreiber K;Kastriti ME;Lönnerberg P;Furlan A;Fan J;Borm LE;Liu Z;van Bruggen D;Guo J;He X;Barker R;Sundström E;Castelo-Branco G;Cramer P;Adameyko I;Linnarsson S;Kharchenko PV
通讯作者：
Kharchenko PV