Wedel, J.; Kochupurakkal, N.; Kong, S. W.; Bose, S.; Lee, J.-W.; Maslyar, M.; Alsairafi, B.; Macleod, K.; Liu, K.; Zhang, H.; Komatsu, M.; Nakayama, H.; Bielenberg, D. R.; Briscoe, D.

Co-inhibitory 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 NRP2 is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is co-expressed with established co-inhibitory 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 co-inhibitory molecule. Knockout of NRP2 resulted in hyperactive CD4+ T cell responses, and enhanced inflammation in delayed type hypersensitivity and transplantation models. Following cardiac transplantation, allograft rejection and graft failure was accelerated in global as well as CD4+ T cell-specific knockout recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4+ T effectors, and not on CD4+Foxp3+ T regulatory cells. Also, knockout T regulatory cells were found to be as efficient as wild type cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a novel coinhibitory receptor and demonstrate that its expression on CD4+ T effector cells is of great functional importance in immunity.