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One of the key drivers of this increased susceptibility is the progressive decline in immune function\u2014immunosenescence that reshapes the host\u2019s inflammatory landscape. Emerging evidence points to an age-associated expansion of cytotoxic CD4+ T cells (CD4 CTLs), which can play context-dependent protective or pathogenic roles in host homeostasis and disease, reflecting their unique integration of helper and cytotoxic programs as well as their preferential expansion during aging. On the protective side, CD4 CTLs contribute to immune surveillance and host defense against viral infections and malignancies. Conversely, in selected settings, they can function as pathogenic effectors in autoimmune and neurodegenerative disorders. In this review, we synthesize the emerging biology of CD4 CTLs, highlighting their differentiation and dual roles in protection and pathology. Beyond a descriptive overview, we propose a conceptual framework that places age-associated CD4 CTL expansion at the intersection of aging and age-associated disease. Rather than viewing late-life pathologies as fully independent events, we suggest that at least a subset may be partially interconnected by recurrent CD4 CTL programs, while emphasizing that the strength of evidence and the degree of causality differ substantially by disease context. This framework provides a basis for asking when CD4 CTLs should be enhanced, restrained, or more precisely redirected to promote healthy longevity.<\/jats:p>","DOI":"10.1093\/intimm\/dxag037","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T11:25:25Z","timestamp":1783941925000},"page":"665-689","source":"Crossref","is-referenced-by-count":0,"title":["Cytotoxic CD4+ T cells across aging: a conceptual framework for health, protection, pathology, and age-associated diseases"],"prefix":"10.1093","volume":"38","author":[{"given":"Tatsuya","family":"Hasegawa","sequence":"first","affiliation":[{"name":"Department of Dermatology, Kyoto University Graduate School of Medicine , 54 Shogoin-Kawara, Sakyo-ku, Kyoto 606-8507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosei","family":"Nishitani","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Kyoto University Graduate School of Medicine , 54 Shogoin-Kawara, Sakyo-ku, Kyoto 606-8507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-0554","authenticated-orcid":false,"given":"Kenji","family":"Kabashima","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Kyoto University Graduate School of Medicine , 54 Shogoin-Kawara, Sakyo-ku, Kyoto 606-8507 ,","place":["Japan"]},{"name":"A*STAR Skin Research Labs (A*SRL), Singapore Immunology Network (SIgN), and Skin Research Institute of Singapore (SRIS), Agency for Science, Technology, and Research (A*STAR) , Biopolis 138648 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"2026103105362930600_dxag037-B1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aeb2970","article-title":"Age-related thymic involution: mechanistic insights and rejuvenating approaches to restore immune function","volume":"12","author":"Santamaria","year":"2026","journal-title":"Sci Adv"},{"key":"2026103105362930600_dxag037-B2","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/s43587-021-00114-7","article-title":"SARS-CoV-2, COVID-19 and the ageing immune system","volume":"1","author":"Bartleson","year":"2021","journal-title":"Nat Aging"},{"key":"2026103105362930600_dxag037-B3","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/s41577-026-01269-3","article-title":"The ageing immune system as a driver of systemic ageing","volume":"26","author":"Jang","year":"2026","journal-title":"Nat Rev Immunol"},{"key":"2026103105362930600_dxag037-B4","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1038\/nri3152","article-title":"Expanding roles for CD4(+) T cells in immunity to viruses","volume":"12","author":"Swain","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"2026103105362930600_dxag037-B5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.119.4.1365","article-title":"Induction of I region-restricted hapten-specific cytotoxic T lymphocytes","volume":"119","author":"Wagner","year":"1977","journal-title":"J Immunol"},{"key":"2026103105362930600_dxag037-B6","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1084\/jem.162.1.171","article-title":"Expression of specific cytolytic activity by H-2I region-restricted, influenza virus-specific T lymphocyte clones","volume":"162","author":"Lukacher","year":"1985","journal-title":"J Exp Med"},{"key":"2026103105362930600_dxag037-B7","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1002\/eji.1830240611","article-title":"Assessment of alloreactive T cell subpopulations of aged mice in vivo. 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