TCR signaling induces STAT3 phosphorylation to promote TH17 cell differentiation.
J Exp Med
; 221(3)2024 Mar 04.
Article
de En
| MEDLINE
| ID: mdl-38324068
ABSTRACT
TH17 differentiation is critically controlled by "signal 3" of cytokines (IL-6/IL-23) through STAT3. However, cytokines alone induced only a moderate level of STAT3 phosphorylation. Surprisingly, TCR stimulation alone induced STAT3 phosphorylation through Lck/Fyn, and synergistically with IL-6/IL-23 induced robust and optimal STAT3 phosphorylation at Y705. Inhibition of Lck/Fyn kinase activity by Srci1 or disrupting the interaction between Lck/Fyn and STAT3 by disease-causing STAT3 mutations selectively impaired TCR stimulation, but not cytokine-induced STAT3 phosphorylation, which consequently abolished TH17 differentiation and converted them to FOXP3+ Treg cells. Srci1 administration or disrupting the interaction between Lck/Fyn and STAT3 significantly ameliorated TH17 cell-mediated EAE disease. These findings uncover an unexpected deterministic role of TCR signaling in fate determination between TH17 and Treg cells through Lck/Fyn-dependent phosphorylation of STAT3, which can be exploited to develop therapeutics selectively against TH17-related autoimmune diseases. Our study thus provides insight into how TCR signaling could integrate with cytokine signal to direct T cell differentiation.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Récepteurs aux antigènes des cellules T
/
Encéphalomyélite auto-immune expérimentale
/
Cellules Th17
Limites:
Animals
Langue:
En
Journal:
J Exp Med
/
J. exp. med
/
Journal of experimental medicine
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine
Pays de publication:
États-Unis d'Amérique