Tissue-resident [PSGL1.sup.lo][CD4.sup.+] T cells promote B cell differentiation and chronic graft-versus-host disease-associated autoimmunity

[CD4.sup.+] 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.sup.hi][CD62L.sup.lo][PSGL1.sup.lo][CD4.sup.+] T cells ([PSGL1.sup.lo][CD4.sup.+] T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized [MHC.sup.-/-][HLA-A2.sup.+][DR4.sup.+] murine models of cGVHD, we showed that murine and human [PSGL1.sup.lo][CD4.sup.+] 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.sup.lo][CD4.sup.+] 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.sup.lo][CD4.sup.+] T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human [PSGL1.sup.lo][CD4.sup.+] 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.
Introduction Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and chronic graft-versus-host disease (cGVHD) are mediated by abnormal [CD4.sup.+] T cell interaction with B cells and autoantibody deposition in [...]