Tissue-resident PSGL1(lo)CD4(+) 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.