Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host disease–associated autoimmunity

摘要

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 CD44~(hi)CD62L~(lo)PSGL1~(lo)CD4~(+) T cells (PSGL1~(lo)CD4~(+) 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 PSGL1~(lo)CD4~(+) 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 PSGL1~(lo)CD4~(+) 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 PSGL1~(lo)CD4~(+) T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1~(lo)CD4~(+) 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.