Tissue-Resident PSGL1^loCD4⁺ T Cells Interact with B Cells Via PD-1 and PD-L2 in Gvhd Target Tissues to Augment Autoimmune-like Chronic Gvhd

Chronic graft versus host disease (cGVHD) is a systemic autoimmune-like syndrome, and donor-type CD4⁺ T interaction with B cells plays an important role in its pathogenesis. Our recent publication has demonstrated that cGVHD pathogenesis does not require germinal center formation and is associated with expansion of extrafollicular CD44^hiCD62L^loPSGL1^loCD4⁺ (PSGL1^loCD4⁺) T cells in the spleen and GVHD target tissues. The causal role of PSGL1^loCD4⁺ T cells in cGVHD pathogenesis remains unclear. With murine and humanized murine models, we show that both murine and human PSGL1^loCD4⁺ T cells reside in tissues and do not circulate in the blood, and their high expression of PD-1 and ICOS and production of IL-21 suggest that they provide B cell help. In murine models, PSGL1^loCD4⁺ T cells augment plasma cell expansion and autoantibody production via their PD-1 interaction with PD-L2 on B. In humanized mouse models, human PSGL1^loCD4⁺ T cells from GVHD target tissues augment memory B cell differentiation into plasma cells and antibody production via their production of IL-21.These results indicate that tissue-resident PSGL1^loCD4⁺ T cells augment autoantibody production and cGVHD pathogenesis. Targeting tissue-resident T cells may represent a novel approach for treating cGVHD.