CD4⁺CD57⁺ senescent T cells as promoters of systemic lupus erythematosus pathogenesis and the therapeutic potential of senolytic BCL‐2 inhibitor

Abstract

Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune‐mediated 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 + CD57 + senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B‐lymphoma‐2 (BCL‐2) family and interferon‐induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL‐15 stimulation increased the frequency of senescent CD4 + T cells and upregulated the expression of BCL‐2 family and ISGs. Further, treatment with ABT‐263 (a senolytic BCL‐2 inhibitor) in MRL/ lpr mice resulted in decreased: (1) frequency of CD4 + CD44 hi CD62L − PD‐1 + CD153 + senescent CD4 + T cells; (2) frequency of CD19 + CD11c + T‐bet + age‐related 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 + CD57 + senescent CD4 + T cells in the pathogenesis of SLE and senolytic BCL‐2 inhibitor ABT‐263 may be the potential treatment in ameliorating lupus phenotypes.