Deciphering the key regulatory factor of CXCL13+ human CD4 T cells 4487

Abstract Description CXCL13 is a key chemokine that recruits CXCR5+ immune cells to inflamed peripheral tissues and drives ectopic lymphoid structure (ETS) formation in cancers and autoimmune diseases. Recent findings show that terminally differentiated CD4+ T cells, distinct from T follicular helper cells, are a source of CXCL13 in human inflammatory tissues, altering the paradigm of ETS development. However, the factors regulating CXCL13 expression in these CD4+ T cells remain unclear. We investigated TNF superfamily ligands involved in early ETS formation and identified that OX40L, a costimulatory molecule essential for germinal center formation, in combination with TGF-β1 under exhaustive stimulation, drives CXCL13 expression in human CD4+ T cells. Temporal network analysis of single-cell and bulk transcriptomics revealed transcription factors (TFs) regulating T cell differentiation and effector function. Lentiviral knockdowns of candidate TFs showed that AP-1 and IRF family members, particularly IRF4 and c-JUN, specifically regulate CXCL13 expression independent of T cell activation. Our findings suggest that in TGF-β1-enriched environments, OX40-OX40L signaling, mediated by AP-1 and IRF TFs, induces CXCL13 in CD4+ T cells. This pathway represents a potential therapeutic target for treating chronic inflammatory diseases. Funding Sources This work was supported by grants to N.T.C. from NIAID/NIH (T32 AI155387), by the National Multiple Sclerosis Society (NMSS) (Harry Weaver Award: JF-2208-40314) and Race to Erase MS Young investigator award to T.S.S.; NIH grants (P01 AI073748, P01 AI039671) and the Nancy Taylor Foundation for Chronic Diseases and Race to Erase MS to D.A.H. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)