Abstract
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 accelerated in global as well as CD4+ T cell–specific KO recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4+ T effectors but not on CD4+Foxp3+ Tregs. Also, KO Tregs were found to be as efficient as WT cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a potentially novel coinhibitory receptor and demonstrate that its expression on CD4+ T effector cells is of great functional importance in immunity.
Authors
Johannes Wedel, Nora Kochupurakkal, Sek Won Kong, Sayantan Bose, Ji-Won Lee, Madeline Maslyar, Bayan Alsairafi, Kayla MacLeod, Kaifeng Liu, Hengcheng Zhang, Masaki Komatsu, Hironao Nakayama, Diane R. Bielenberg, David M. Briscoe
Figure 6
NRP2 expression on CD4+ T effector cells is required for long-term allograft survival.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)