Stability and function of regulatory T cells is maintained by a neuropilin-1–semaphorin-4a axis

• Published in: Nature (London) Vol. 501; no. 7466; pp. 252 - 256
• Main Authors: Delgoffe, Greg M., Woo, Seng-Ryong, Turnis, Meghan E., Gravano, David M., Guy, Cliff, Overacre, Abigail E., Bettini, Matthew L., Vogel, Peter, Finkelstein, David, Bonnevier, Jody, Workman, Creg J., Vignali, Dario A. A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2013; Nature Publishing Group
• Subjects: 631/250/1619/554/1898/1271; Animals; Autoimmune diseases; Autoimmunity - immunology; Cell adhesion & migration; Cell Survival; Colitis - immunology; Female; Forkhead Box Protein O3; Forkhead Transcription Factors - metabolism; HEK293 Cells; Homeostasis; Homeostasis - immunology; Humanities and Social Sciences; Humans; Immune system; Immune Tolerance - immunology; Immunological Synapses; Immunology; Immunosuppression; Kinases; Laboratory animals; letter; Lymphocytes; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Melanoma; Mice; Mice, Inbred C57BL; multidisciplinary; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Neuropilin-1 - deficiency; Neuropilin-1 - metabolism; Phosphorylation; Physiological aspects; Properties; Proteins; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; Rodents; Science; Semaphorins; Semaphorins - metabolism; Signal Transduction; T cells; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; TOR Serine-Threonine Kinases - metabolism; Vascular endothelial growth factor; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature12428

Neuropilin-1 (Nrp1) on regulatory T (T reg ) cells is shown to interact with semaphorin-4a (Sema4a) to promote a program of T reg -cell stability and survival, in part through PTEN-mediated modulation of Akt signalling; Nrp1-deficient T reg cells can maintain immune homeostasis but fail to suppress in inflammatory sites, such as tumours, providing an attractive immunotherapeutic target for the treatment of cancers. Anti-tumour versus pro-immunity effects of T reg cells Regulatory T cells (T reg ) constitute a barrier to effective anti-tumour immunity. Their depletion can induce reduction and clearance of many tumours, but as the cells perform an important balancing role in the immune system, depletion also results in unchecked autoimmunity and death. This paper describes an interaction between semaphorin-4a — an activator for T-cell-mediated immunity — and the neuropilin receptor Nrp1 on T reg cells that is required for T reg cells to limit anti-tumour immune responses and to cure established inflammatory colitis, but is dispensable for suppression of autoimmunity and maintenance of immune homeostasis. It remains to be determined whether it is feasible to limit tumour growth by targeting T reg cells without unleashing autoimmunity. The two biological activities may be inseparable, but this work points to ways in which this important system can be further characterized. Regulatory T cells (T reg cells) have 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-tumour immunity and sterilizing immunity to chronic viral infections 1 . The transcription factor Foxp3 has a major role in the development and programming of T reg cells 2 , 3 . The relative stability of T reg cells at inflammatory disease sites has been a highly contentious subject 4 , 5 , 6 . There is considerable interest in identifying pathways that control the stability of T reg cells as many immune-mediated diseases are characterized by either exacerbated or limited T reg -cell function. Here we show that the immune-cell-expressed ligand semaphorin-4a (Sema4a) and the T reg -cell-expressed receptor neuropilin-1 (Nrp1) interact both in vitro , to potentiate T reg -cell function and survival, and in vivo , at inflammatory sites. Using mice with a T reg -cell-restricted deletion of Nrp1, we show that Nrp1 is dispensable for suppression of autoimmunity and maintenance of immune homeostasis, but is required by T reg cells to limit anti-tumour immune responses and to cure established inflammatory colitis. Sema4a ligation of Nrp1 restrained Akt phosphorylation cellularly and at the immunologic synapse by phosphatase and tensin homologue (PTEN), which increased nuclear localization of the transcription factor Foxo3a. The Nrp1-induced transcriptome promoted T reg -cell stability by enhancing quiescence and survival factors while inhibiting programs that promote differentiation. Importantly, this Nrp1-dependent molecular program is evident in intra-tumoral T reg cells. Our data support a model in which T reg -cell 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 -cell-mediated tumour-induced tolerance without inducing autoimmunity.