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CCR6 signaling inhibits suppressor function of induced-Treg during gut inflammation

Neeraja Kulkarni1, Heikrujam Thoihen Meitei1, Sandip Ashok Sonar1

  • 1National Centre for Cell Science, Pune, MH 411007, India.

Journal of Autoimmunity
|November 12, 2017
PubMed

Insights

CCR6 signaling impacts immune cell differentiation during gut inflammation. This study reveals CCR6 promotes pathogenic T cell development, impairing regulatory T cell function in ulcerative colitis patients.

Area of Science:

  • Immunology
  • Cell Biology
  • Gastroenterology

Background:

  • CCR6 (C-C chemokine receptor type 6) and its ligand CCL20 are known to mediate immune cell migration.
  • The non-chemotactic roles of CCR6 signaling, particularly in T cell differentiation during inflammation, remain largely unexplored.

Purpose of the Study:

  • To investigate the novel functions of CCR6 signaling in T regulatory cell (Treg) differentiation and function during gut inflammation.
  • To explore the role of CCR6-CCL20 axis in the pathogenesis of ulcerative colitis (UC).

Main Methods:

  • Analysis of T cell populations, including Foxp3+CD4+ T cells (Tregs), in secondary lymphoid tissues and peripheral blood mononuclear cells (PBMCs) from UC patients and healthy individuals.
  • Assessment of RORγt expression in CCR6+ Tregs.
  • In vitro studies on TGF-β1-induced Treg (iTreg) differentiation in the presence of CCL20, evaluating lineage commitment, surface marker expression (CD39, CD73, FasL), and suppressive function.
  • Investigation of intracellular signaling pathways, including Akt, mTOR, and STAT3 phosphorylation, in T cells upon CCR6 signaling.

Main Results:

  • Reduced frequency of Foxp3+CD4+ T cells in secondary lymphoid tissues during gut inflammation.
  • Elevated RORγt expression in CCR6+ Tregs, particularly in UC patients.
  • CCL20 inhibited iTreg differentiation and promoted a pathogenic Th17-like lineage commitment in a CCR6-dependent manner.
  • CCL20-treated iTregs exhibited reduced expression of suppressive molecules and impaired suppressive capacity.
  • CCR6 signaling activated Akt, mTOR, and STAT3 pathways in T cells.

Conclusions:

  • CCR6 signaling plays a critical, non-chemotactic role in regulating T cell differentiation during gut inflammation.
  • The CCR6-CCL20 axis contributes to the imbalance of immune cells seen in ulcerative colitis by impairing Treg function and promoting pathogenic T cell lineages.
  • These findings identify CCR6 as a potential therapeutic target for modulating immune responses in inflammatory gut diseases.
Keywords:
Autoimmune colitisCCR6Foxp3Inflammatory bowel diseaseRORγtTregs

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