Regulatory T cell stability is maintained by a neuropilin-1:semaphorin-4a axis

Regulatory T cells (T(regs)) play a crucial role in the immune system by preventing autoimmunity, limiting immunopathology, and maintaining immune homeostasis(1). However, they also represent a major barrier to effective anti-tumor immunity and sterilizing immunity to chronic viral infections(1). The transcription factor Foxp3 plays a major role in the development and programming of T(reg) cells(2,3). The relative stability of T(regs) at inflammatory disease sites has been highly contentious(4-6). There is considerable interest in identifying pathways that control T(reg) stability as many immune-mediated diseases are characterized by either exacerbated or limited T(reg) function. Here we show that the immune cell-expressed ligand semaphorin-4a (Sema4a) and the T(reg)-expressed receptor neuropilin-1 (Nrp1) interact to potentiate T(reg) function and survival in vitro and in inflammatory sites in vivo. Nrp1 is dispensable for suppression of autoimmunity and maintenance of immune homeostasis, but is required by T(regs) to limit anti-tumor immune responses and to cure established inflammatory colitis. Sema4a ligation of Nrp1 restrained Akt phosphorylation cellularly and at the immunologic synapse (IS) via phosphatase and tensin homolog (PTEN), which increased nuclear localization of the transcription factor Foxo3a. The Nrp1-induced transcriptome promoted T(reg) stability by enhancing quiescence/survival factors while inhibiting programs that promote differentiation. Importantly, this Nrp1-dependent molecular program is evident in intratumoral T(regs). Our data support a model in which T(reg) stability can be subverted in certain inflammatory sites, but is maintained by a Sema4a:Nrp1 axis, highlighting this pathway as a potential therapeutic target that could limit T(reg)-mediated tumor-induced tolerance without inducing autoimmunity.