2025/01/22 by Hila Novak Kotzer, Jesusa Capera, Ashwin Jainarayanan +6 · 1 voice
Immunology and Microbiology · Medicine · #Cytokine Signaling Pathways and Interactions #Immunodeficiency and Autoimmune Disorders #Rheumatoid Arthritis Research and Therapies
paper · doi:10.1101/2025.01.20.633875
openalex publication_date 2025/01/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/14
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 naïve 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.