biostudies-literatureWedel JNIH NIAIDIsabella Julian Forrest FoundationCasey Lee Ball Foundatione172218https://www.ebi.ac.uk/biostudies/studies/S-EPMC12208552biostudies-literatureUnknown135(13)Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin-2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule. Knockout (KO) of NRP2 resulted in hyperactive CD4+ T cell responses and enhanced inflammation in delayed-type hypersensitivity and transplantation models. After cardiac transplantation, allograft rejection and graft failure were The Journal of clinical investigationNeuropilin-2 functions as a coinhibitory receptor to regulate antigen-induced inflammation and allograft rejection.PMC12208552N/AR01AI148539Nakayama HBriscoe DMBose SLiu KZhang HMacLeod KWedel JLee JWBielenberg DRKochupurakkal NMaslyar MKong SWAlsairafi BKomatsu MfalseNeuropilin-2 functions as a coinhibitory receptor to regulate antigen-induced inflammation and allograft rejection.Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin-2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule. Knockout (KO) of NRP2 resulted in hyperactive CD4+ T cell responses and enhanced inflammation in delayed-type hypersensitivity and transplantation models. After cardiac transplantation, allograft rejection and graft failure were 2025-01-01T00:00:00Z2025 Jul2026-06-01T15:31:49.139Z2026-04-08T13:44:39.872ZS-EPMC122085524059022410.1172/JCI172218