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The accumulation of senescent T and B cells has been observed in SLE and other immune\u2010mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4<jats:sup>+<\/jats:sup>CD57<jats:sup>+<\/jats:sup> senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B\u2010lymphoma\u20102 (BCL\u20102) family and interferon\u2010induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL\u201015 stimulation increased the frequency of senescent CD4<jats:sup>+<\/jats:sup> T cells and upregulated the expression of BCL\u20102 family and ISGs. Further, treatment with ABT\u2010263 (a senolytic BCL\u20102 inhibitor) in MRL\/<jats:italic>lpr<\/jats:italic> mice resulted in decreased: (1) frequency of CD4<jats:sup>+<\/jats:sup>CD44<jats:sup>hi<\/jats:sup>CD62L<jats:sup>\u2212<\/jats:sup>PD\u20101<jats:sup>+<\/jats:sup>CD153<jats:sup>+<\/jats:sup> senescent CD4<jats:sup>+<\/jats:sup> T cells; (2) frequency of CD19<jats:sup>+<\/jats:sup>CD11c<jats:sup>+<\/jats:sup>T\u2010bet<jats:sup>+<\/jats:sup> age\u2010related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4<jats:sup>+<\/jats:sup>CD57<jats:sup>+<\/jats:sup> senescent CD4<jats:sup>+<\/jats:sup> T cells in the pathogenesis of SLE and senolytic BCL\u20102 inhibitor ABT\u2010263 may be the potential treatment in ameliorating lupus phenotypes.<\/jats:p>","DOI":"10.1002\/eji.202350603","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T08:39:35Z","timestamp":1715848775000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["CD4<sup>+<\/sup>CD57<sup>+<\/sup> senescent T cells as promoters of systemic lupus erythematosus pathogenesis and the therapeutic potential of senolytic BCL\u20102 inhibitor"],"prefix":"10.1002","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3916-1712","authenticated-orcid":false,"given":"Jiao","family":"Jiang","sequence":"first","affiliation":[{"name":"Hospital for Skin Diseases, Institute of Dermatology Chinese Academy of Medical Sciences &amp; 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