Neuropilin-2 functions as a co-inhibitory receptor to regulate antigen-induced inflammation and allograft rejection

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.