DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions.
Adoptive Transfer
Animals
Antigens, Differentiation, T-Lymphocyte
/ genetics
Forkhead Transcription Factors
/ genetics
Gene Expression Regulation
Graft vs Host Disease
/ genetics
Humans
Immune Tolerance
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Protein Binding
Proto-Oncogene Proteins c-akt
/ genetics
Receptors, Immunologic
/ genetics
Receptors, Virus
/ genetics
Signal Transduction
T-Lymphocytes, Regulatory
/ immunology
TOR Serine-Threonine Kinases
/ genetics
Whole-Body Irradiation
DNAM-1
Foxp3
TIGIT
mTORC1
regulatory T (Treg) cells
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
25 05 2021
25 05 2021
Historique:
entrez:
20
5
2021
pubmed:
21
5
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
Regulatory T (Treg) cells that express forkhead box P3 (Foxp3) are pivotal for immune tolerance. Although inflammatory mediators cause Foxp3 instability and Treg cell dysfunction, their regulatory mechanisms remain incompletely understood. Here, we show that the transfer of Treg cells deficient in the activating immunoreceptor DNAM-1 ameliorated the development of graft-versus-host disease better than did wild-type Treg cells. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to their common ligand CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function without DNAM-1-mediated intracellular signaling. DNAM-1 deficiency augments TIGIT signaling; this subsequently inhibits activation of the protein kinase B-mammalian target of rapamycin complex 1 pathway, resulting in the maintenance of Foxp3 expression and Treg cell function under inflammatory conditions. These findings demonstrate that DNAM-1 regulates Treg cell function via TIGIT signaling and thus, it is a potential molecular target for augmenting Treg function in inflammatory diseases.
Identifiants
pubmed: 34011606
pii: 2021309118
doi: 10.1073/pnas.2021309118
pmc: PMC8166105
pii:
doi:
Substances chimiques
Antigens, Differentiation, T-Lymphocyte
0
CD226 antigen
0
Forkhead Transcription Factors
0
Foxp3 protein, mouse
0
Receptors, Immunologic
0
Receptors, Virus
0
T cell Ig and ITIM domain protein, mouse
0
poliovirus receptor
0
mTOR protein, mouse
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
Competing interest statement: A.S. and K. Shibuya have stock in TNAX Biopharma Corporation.
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