The NOTCH-HES-1 axis is involved in promoting Th22 cell differentiation

Background NOTCH signaling has been shown to play a role in the production of interleukin-22 (IL-22) by CD4(+) T cells. Multiple T-helper (Th) cell populations secrete IL-22. Th22 (CD4(+)IL22(+)IFN gamma(-)IL17A(-)) cells are a subgroup of CD4(+) effector T cells that primarily generate IL-22. The regulatory mechanisms of the NOTCH signaling pathway involved in differentiation of the Th22 cell subset have not been completely elucidated. This study aimed to further explore the involvement of NOTCH signaling in Th22 differentiation. Methods In vitro combination of IL-6, IL-23, and tumor necrosis factor-alpha (TNF-alpha) treatment with naive CD4(+) T cells established the Th22 cell induced model. NOTCH signaling was activated by jagged-1 and inhibited by (2S)-N-[(3,5-difluorophenyl) acetyl]-L-alanyl-2-phenyl]glycine 1,1-dimethylethyl ester (DAPT). HES-1 siRNA and HES-1 vector were employed to knock down and induce overexpression of HES-1 to investigate the effect of NOTCH signaling on the differentiation of CD4(+)T cells into Th22 cells. Results We observed that the proportion of Th22 cells, along with Hes-1, Ahr, and Il-22 mRNA and protein expression, was increased by both jagged-1 and overexpression of HES-1. On the other hand, after the combined cytokine treatment of cells, and exposure to jagged-1 and DAPT or HES-1 siRNA, there was a decrease in the Th22 cell proportion, mRNA and protein expression of HES-1, AHR, and IL-22. Conclusions Our study demonstrates that HES-1 enhancement in AHR and IL-22 up-regulation of NOTCH signaling can promote the skewing of naive CD4(+)T cells toward Th22 cells. Also, the results of our study show that HES-1 is a crucial factor in Th22 cell differentiation.

Automated summary

This study indicates the regulatory role of NOTCH signaling in Th22 cell differentiation, highlighting the importance of HES-1 in the upregulation of AHR and IL-22. Enhancing HES-1 through NOTCH signaling promotes naive CD4(+) T cell skewing towards Th22 cells.