TY - JOUR AU - Kong, Xiaohui AU - Zeng, Deye AU - Wu, Xiwei AU - Wang, Bixin AU - Yang, Shijie AU - Song, Qingxiao AU - Zhu, Yongping AU - Salas, Martha AU - Qin, Hanjun AU - Nasri, Ubaydah AU - Haas, Karen M. AU - Riggs, Arthur D. AU - Nakamura, Ryotaro AU - Martin, Paul J. AU - Huang, Aimin AU - Zeng, Defu T1 - Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host disease–associated autoimmunity PY - 2021/01/04/ AB - CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC–/–HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2–dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI135468 VL - 131 IS - 1 UR - https://doi.org/10.1172/JCI135468 PB - The American Society for Clinical Investigation ER -