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Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3+

Ding Wang1, Hanjun Qin, Weiting Du

  • 1Department of Diabetes and Metabolic Diseases, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 31, 2012
PubMed

Insights

Skp2, an E3 ubiquitin ligase, critically regulates pathogenic T cells (Tpaths) and regulatory T cells (Tregs). Down-regulating Skp2 converts Tpaths into suppressive Tregs, offering insights into autoimmune disease regulation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Distinct gene profiles differentiate autoreactive pathogenic T cells (Tpaths) and regulatory T cells (Tregs).
  • The specific genes and pathways governing Tpath vs. Treg functional determination remain largely unknown.
  • Understanding these mechanisms is crucial for modulating immune responses in autoimmune diseases.

Purpose of the Study:

  • To investigate the role of Skp2, an E3 ubiquitin ligase, in the functional specification of Tpaths and Tregs.
  • To elucidate the molecular mechanisms by which Skp2 influences Tpath-Treg conversion and immune tolerance.

Main Methods:

  • Studied the function of Skp2 in diabetogenic Tpaths and Tregs.
  • Manipulated Skp2 expression levels (down-regulation and overexpression) in T cells.
  • Analyzed gene expression changes, including cell cycle regulators and Foxo family genes.
  • Assessed T cell suppressive function, proliferation, and activation-induced cell death.
  • Utilized non-obese diabetic (NOD) mice models to evaluate in vivo effects.

Main Results:

  • Down-regulation of Skp2 in diabetogenic Tpaths induced their conversion into Foxp3-expressing Tregs.
  • These converted Tregs exhibited suppressive functions dependent on TGF-β/IL-10 production and inhibited diabetes in NOD mice.
  • Skp2 down-regulation led to Treg conversion partly via up-regulation of cell cycle control genes and Foxo family genes.
  • Down-regulation of p27, p21, Foxo1, and Foxo3 modulated Skp2's effect on Tpath-Treg conversion and suppressive function.
  • Skp2 overexpression abrogated nTreg suppressive function and decreased Foxp3 expression.

Conclusions:

  • Skp2 plays a critical role in the functional specification of Tpaths and Tregs.
  • Skp2 modulates immune tolerance by regulating Tpath-Treg balance, offering a potential therapeutic target for autoimmune diseases.
  • The findings reveal a key molecular mechanism involving Skp2 in controlling T cell fate and function.

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