Patched 1 and C-C Motif Chemokine Receptor 6 Distinguish Heterogeneous T Helper 17 Subsets in Colitic Lamina Propria

ABSTRACT

T helper 17 (Th17) cells contribute to the pathogenesis of inflammatory bowel diseases (IBD). However, their heterogeneity and regulatory mechanisms in IBD are not completely disclosed. A mouse colitis model was established. Th17 cells were enriched from the mesenteric lymph nodes (mLN) and lamina propria (LP). The phenotypes and functions of Th17 subsets were analyzed by flow cytometry, Immunoblotting, and real-time RT-PCR. The contributions of the Th17 subsets to colitis pathogenesis were evaluated by histology, ELISA, and flow cytometry after adoptive transfer. Smoothened (SMO), GLI family zinc finger 1 (Gli1), and GLI family zinc finger 3 (Gli3) were markedly up-regulated while Patched 1 (PTCH1) was down-regulated in LP Th17 cells in colitic lamina propria. Based on the expression of PTCH1 and C-C motif chemokine receptor 6 (CCR6), LP Th17 cells were divided into a PTCH1^lowCCR6^low Th17 subset and a PTCH1^highCCR6^high Th17 subset. The former expressed higher T-bet, IFN-γ, TNF-α, IL-1β, and GM-CSF but lower IL-17A, IL-22, IL-17F, and Gli3 than the latter. The PTCH1^highCCR6^high Th17 subset was more resistant to polarization towards T helper 1 (Th1) than the PTCH1^lowCCR6^low Th17 subset. Moreover, the PTCH1^highCCR6^high Th17 subset was more competent to maintain Th17 identity. The PTCH1^highCCR6^high Th17 subset induced less severe colitis than the PTCH1^lowCCR6^low Th17 subset. PTCH1^highCCR6^high Th17 cells are Th17 cells whereas PTCH1^lowCCR6^low Th17 cells are Th1-like Th17 cells. Our study deepens the understanding of Th17 heterogeneity and plasticity in colitis.

KEYWORDS:

• C-C motif chemokine receptor 6
• Hedgehog signaling
• inflammatory bowel diseases
• Patched 1
• T helper 17 cells

Author contributions

Shengli Pei: Conceptualization, Methodology, Investigation. Chao Ke: Methodology, Investigation. Jiantao Han: Investigation. Xingwang Xie: Supervision, Validation, Writing- Original draft preparation, Writing- Reviewing and Editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/08820139.2022.2141123

Data availability

The data are available from the corresponding author upon reasonable request.

Additional information

Funding

This study was supported by the Wuhan Clinical Research Foundation (Grant# WX14C22) and Wuhan Municipal Medical Research Foundation (Grant# WX20A07)