CHEMOKINE RECEPTOR CCR6 INTRINSIC SIGNALING ALTERS METABOLIC REPROGRAMMING OF TH17 CELL DURING GUT INFLAMMATION AND AUTOIMMUNITY
- Girdhari Lal, India
Abstract
Background and Aims
CCR6 is a G protein-coupled receptor, and ulcerative colitis patients show strong positive with the severity of the disease. How does CCR6 intrinsic signaling in CD4 T cells affect the pathogenicity of Th17 cells during gut inflammation and autoimmunity is not known.
Methods
Immune cells were phenotypically characterized using flow cytometry. FACS purified naïve CD4 T cells were in vitro differentiated into Th17 in the presence or absence of CCL20, and proteomic analysis was performed using mass spectroscopy. Gut inflammation in wild-type C57BL/6 or CCR6-/- mice was induced by giving dextran sodium sulfate in the drinking water.
Results
Our results showed that ulcerative colitis patients have a significantly high frequency of RORgt+T-bet+CD4+ T cells in PBMCs as compared to healthy individuals. In the presence of CCL20, in vitro differentiation of purified naïve human CD4+ T cells into Th17 cells significantly increased the frequency of pathogenic IL-23R+Th17 cells (IL-17+IFNγ+GMCSF+ Th17 cells) in the AKT/mTOR/STAT3 signaling dependent manner. Furthermore, CCR6-/- mice showed reduced inflammatory colitis and lower frequency of pathogenic Th17 in the gut-associated lymphoid tissues as compared to wild-type mice. Deficiency of CCR6-/- abrogated the CCL20 driven differentiation of pathogenic Th17 cells. Proteomics analysis of Th17 cells differentiated in the presence of CCL20 showed significant alteration in several proteins belonging to various cellular metabolic pathways.
Conclusions
Signaling through the CCL20-CCR6 axis drive the differentiation of pathogenic Th17 cells by altering the cellular metabolism, and a strategy to block the non-chemotactic function of CCR6 may help in controlling the gut inflammation and autoimmunity.