Neuropilin-1 Is Expressed on Highly Activated CD4 Effector T Cells and Dysfunctional CD4 Conventional T Cells from Naive Mice.

Neuropilin-1 (Nrp-1) is a well described marker molecule for CD4Foxp3 thymus-derived regulatory T cells (Tregs). In addition, a small population of CD4Foxp3 conventional (conv) T cells expresses Nrp-1 in naive mice, and Nrp-1 expression has been described to be upregulated on activated CD4 T cells. However, the function of Nrp-1 expression on CD4 non-Tregs still remains elusive. In this study, we demonstrate that Nrp-1 expression was induced upon stimulation of CD4Foxp3 T cells in vitro and during an ongoing immune response in vivo. This activation-induced Nrp-1CD4 T cell subset (iNrp-1) showed a highly activated phenotype in terms of elevated CD25 and CD44 expression, enhanced production of proinflammatory cytokines, and increased proliferation compared with the Nrp-1CD4 counterpart. In contrast, Nrp-1CD4Foxp3 conv T cells from naive mice (nNrp-1) were dysfunctional. nNrp-1CD4 conv T cells upregulated activation-associated molecules to a lesser extent, exhibited impaired proliferation and produced fewer proinflammatory cytokines than Nrp-1CD4 conv T cells upon stimulation in vitro. Moreover, the expression of PD-1 and CTLA-4 was significantly higher on nNrp-1CD4Foxp3 T cells compared with iNrp-1CD4Foxp3 T cells and Nrp-1CD4Foxp3 T cells after stimulation and under homeostatic conditions. Strikingly, transfer of Ag-specific iNrp-1CD4 conv T cells aggravated diabetes development, whereas Ag-specific nNrp-1CD4 conv T cells failed to induce disease in a T cell transfer model of diabetes. Overall, our results indicate that Nrp-1 expression has opposite functions in recently activated CD4 non-Tregs compared with CD4 non-Tregs from naive mice.