Scientist BRIC-National Centre for Cell Science Pune, India
Disclosure(s):
Girdhari Lal, PhD: No financial relationships to disclose
Introduction/Rationale: The chemokine receptor CCR6, a G-protein-coupled receptor, binds to its high-affinity ligand, CCL20. Within the CD4+ T cell population, both Th17 and regulatory T cells express CCR6, allowing them to migrate to regions rich in CCL20 and characterized by inflammation. As CCR6+ T cells move from secondary lymphoid organs into inflamed tissues, they encounter distinct metabolic conditions. The specific factors driving metabolic adaptation within these environments, as well as their influence on effector or regulatory T cell functions, remain incompletely understood.
Methods: Acute colitis was induced in C57BL/6 or CCR6-/- mice by giving dextran sodium sulphate (2% w/v) in the drinking water. Chronic colitis was induced by adoptive transfer of naïve CD4 T cells (CD4+CD25-CD44-CD62L+CD45RBhi cells) in RAG1-/- mice. Cells were analyzed using flow cytometry, immunohistochemical analysis, and RT-PCRs.
Results: During colitis, elevated CCL20 production in the gut facilitates the recruitment of specific immune cells. Our studies demonstrate that intrinsic CCL20-CCR6 signaling within CD4+ T cells enhances the differentiation of pathogenic Th1-like Th17 cells (T-bet+RORγt+, IFN-+IL-17A+) in both murine models and human patients. This pathway triggers rapamycin-sensitive phosphorylation events involving PI3K, Akt, mTORC1, and STAT3, contingent on CCR6 expression. Transcriptomic and proteomic analyses indicate that CCL20 modulates Th17 differentiation by affecting multiple metabolic pathways, particularly those associated with energy metabolism, which is further supported by changes in the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Notably, CCL20 markedly increases glycolytic activity while inhibiting oxidative phosphorylation, thereby promoting the generation of pathogenic Th17 cells.
Conclusion: Our results suggest that changes in Th17 metabolism triggered by CCR6 offer a promising avenue for developing a therapeutic strategy to control gut inflammation and autoimmunity.
