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While pathogenesis has traditionally been attributed primarily to T helper type(Th) 2 cytokines (e.g., Interleukin(IL)-4\/IL-10), this mechanism insufficiently accounts for the observed tissue destruction and progressive fibrosis. Emerging data highlight the extensive, oligoclonally expanded infiltration of CD4+ cytotoxic T lymphocytes (CTLs) deep within lesions. These cells possess dual cytotoxic and profibrotic properties. This review systematically elucidates the role of CD4+ CTLs as a distinct lineage and core effector population. We detail how these cells mediate the pathology linking chronic inflammation and fibrosis through direct cytotoxicity, secretion of profibrotic factors, and complex B-cell interactions. Finally, we assess the clinical potential of CD4+ CTLs as biomarkers of disease activity and as novel therapeutic targets.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1781462","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T07:13:48Z","timestamp":1770880428000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond the Th2 paradigm: CD4+ cytotoxic T lymphocytes as key drivers of tissue damage and fibrosis in IgG4-related 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