Publication Date:
2013-08-06
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867145/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867145/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- AI039480/AI/NIAID NIH HHS/ -- CA21765/CA/NCI NIH HHS/ -- F32 AI098383/AI/NIAID NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 AI039480/AI/NIAID NIH HHS/ -- R01 AI091977/AI/NIAID NIH HHS/ -- T32 AI007610/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Sep 12;501(7466):252-6. doi: 10.1038/nature12428. Epub 2013 Aug 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23913274" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Autoimmunity/immunology
;
Cell Survival
;
Colitis/immunology
;
Female
;
Forkhead Transcription Factors/metabolism
;
HEK293 Cells
;
Homeostasis/immunology
;
Humans
;
Immune Tolerance/immunology
;
Immunological Synapses
;
Lymphocytes, Tumor-Infiltrating/cytology/immunology/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Neoplasms/genetics/immunology/pathology
;
Neuropilin-1/deficiency/*metabolism
;
PTEN Phosphohydrolase/metabolism
;
Phosphorylation
;
Proto-Oncogene Proteins c-akt/metabolism
;
Semaphorins/*metabolism
;
Signal Transduction
;
T-Lymphocytes, Regulatory/cytology/*immunology/*metabolism
;
TOR Serine-Threonine Kinases/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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