SEMA4A ligation of NRP1 promotes Treg-cell survival and suppression of antitumor immunity.
Major finding: SEMA4A ligation of NRP1 promotes Treg-cell survival and suppression of antitumor immunity.
Mechanism: SEMA4A–NRP1 enhances PTEN-mediated inhibition of AKT, inducing FOXO-dependent transcription.
Impact: Suppression of SEMA4A–NRP1 may improve antitumor immune responses without inducing autoimmunity.
Regulatory T (Treg) cells control immune homeostasis and suppress autoimmune and antitumor immune responses. Recent studies have shown that signals provided by conventional T cells potentiate the immunosuppressive function of Treg cells, but the factors and mechanisms that mediate this process remain unclear. Delgoffe and colleagues found that semaphorin 4A (SEMA4A), a ligand that regulates neural development and T-cell activation and is expressed by T cells, interacted with neuropilin 1 (NRP1) expressed on Treg cells and enhanced Treg-cell survival and suppressive function. Nrp1 deficiency in Treg cells did not induce an autoimmune phenotype, indicating that NRP1 is not required for prevention of autoimmunity or maintenance of immune homeostasis. In contrast, Nrp1 deficiency specifically impaired Treg cell function in inflammatory environments such as the intestinal mucosa and tumors. Treg cell–specific Nrp1 deletion or inhibition of SEMA4A–NRP1 signaling in wild-type mice resulted in increased accumulation of cytotoxic intratumoral CD8+ T cells, decreased growth of tumors and lung metastases, and prolonged survival, suggesting that NRP1 signaling is essential for suppression of antitumor immune responses by Treg cells. This potentiation of Treg-cell survival and function was mediated by PTEN-dependent inhibition of AKT phosphorylation at the immunologic synapse in response to SEMA4A ligation of NRP1. Furthermore, inhibition of AKT signaling resulted in decreased nuclear export of the forkhead box O3A (FOXO3A) transcription factor and induction of a transcriptional program that stimulated antiapoptotic genes and downregulated lineage-specific genes, thereby promoting survival and quiescence and limiting terminal differentiation in vitro and in intratumoral Treg cells in vivo. These results establish SEMA4A–NRP1 signaling as a critical regulator of Treg cell stability under inflammatory conditions and suggest that suppression of this pathway may enhance antitumor immunity without stimulating autoimmune responses.