Novak-Kotzer Hila, Capera Jesusa, Jainarayanan Ashwin, Elanchezhian Mirudula, Valvo Salvatore, Mayya Viveka, Zanin-Zhorov Alexandra, Macdonald Joanne, Taylor Peter C, Dustin Michael L
Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, New York, NY, 10016, USA; Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY, UK.
Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY, UK.
J Autoimmun. 2025 Jul;155:103456. doi: 10.1016/j.jaut.2025.103456. Epub 2025 Jul 2.
Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4 T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.
靶向JAK/STAT信号通路已成为治疗类风湿性关节炎（RA）的关键治疗策略。JAK抑制剂可抑制细胞因子介导的信号传导，包括关键的IL-6/STAT3轴，从而有效针对病理过程的不同方面。然而，尽管它们具有临床疗效，但一部分RA患者对JAK抑制仍具有抗性，这突出了对替代方法的需求。在这里，我们确定了一种新的STAT3激活的JAK非依赖性机制，该机制由幼稚CD4 T细胞中免疫突触（IS）的形成触发。我们的数据表明，LCK介导了IS处STAT3的TCR依赖性磷酸化，突出了该途径作为早期T细胞激活以前未被认识的标志。此外，我们表明RA中突触LCK/TCR-STAT3途径受损。这一发现突出了JAK抑制剂之外RA的新治疗靶点，为治疗对当前疗法耐药的患者提供了潜在途径。
