Journal Article

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

Zhang, Hengcheng, Bielenberg, Diane R., Maslyar, Madeline, Bose, Sayantan, Kong, Sek Won, Liu, Kaifeng, Komatsu, Masaki, MacLeod, Kayla, Nakayama, Hironao, Wedel, Johannes, Lee, Ji-Won, Alsairafi, Bayan, Briscoe, David M., Kochupurakkal, Nora

2025

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Allografts / Animal models / Animals / Antigens / Antigens, CD - genetics / Antigens, CD - immunology / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - pathology / Cell cycle / Cell receptors / CTLA-4 protein / Effector cells / Flow cytometry / Foxp3 protein / Graft rejection / Graft Rejection - genetics / Graft Rejection - immunology / Graft Rejection - pathology / Health aspects / Heart / Heart Transplantation / Heart transplants / Homeostasis / Humans / Hypersensitivity (delayed) / Immune response / Immunological memory / Immunology / Inflammation / Inflammation - genetics / Inflammation - immunology / Inflammation - pathology / Lymphocytes / Lymphocytes T / Memory cells / Mice / Mice, Knockout / Mice, SCID / Neuromodulation / Neuropilin / Neuropilin-2 - genetics / Neuropilin-2 - immunology / PD-1 protein / Phenotypes / Physiological aspects / Receptor mechanisms / Receptors, Immunologic - genetics / Receptors, Immunologic - immunology / T cell receptors / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - pathology / Transplantation