Year: 2025
Type: article
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)
Source: The Journal of Immunology
Institution: Yale University
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416449799
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