title: Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis.
abstract: Regulatory T cells (Treg cells) have a crucial role in the immune system by preventing autoimmunity, limiting immunopathology, and maintaining immune homeostasis. However, they also represent a major barrier to effective anti-tumour immunity and sterilizing immunity to chronic viral infections. The transcription factor Foxp3 has a major role in the development and programming of Treg cells. The relative stability of Treg cells at inflammatory disease sites has been a highly contentious subject. There is considerable interest in identifying pathways that control the stability of Treg cells as many immune-mediated diseases are characterized by either exacerbated or limited Treg-cell function. Here we show that the immune-cell-expressed ligand semaphorin-4a (Sema4a) and the Treg-cell-expressed receptor neuropilin-1 (Nrp1) interact both in vitro, to potentiate Treg-cell function and survival, and in vivo, at inflammatory sites. Using mice with a Treg-cell-restricted deletion of Nrp1, we show that Nrp1 is dispensable for suppression of autoimmunity and maintenance of immune homeostasis, but is required by Treg 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 Treg-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 Treg cells. Our data support a model in which Treg-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 Treg-cell-mediated tumour-induced tolerance without inducing autoimmunity.
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Delgoffe
authors.forename: Seng-Ryong
authors.initials: SR
authors.lastname: Woo
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Turnis
authors.forename: David M
authors.initials: DM
authors.lastname: Gravano
authors.forename: Cliff
authors.initials: C
authors.lastname: Guy
authors.forename: Abigail E
authors.initials: AE
authors.lastname: Overacre
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Bettini
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Jody
authors.initials: J
authors.lastname: Bonnevier
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002470:Cell Survival; D003092:Colitis / Q000276:immunology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D054992:Immunological Synapses; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D039942:Neuropilin-1 / Q000172:deficiency / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C574096:SEMA4A protein, human; C534721:Sema4A protein, mouse; D039961:Semaphorins; D039942:Neuropilin-1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase
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