Editors' ChoiceImmunology

A Linchpin for Metabolism and Immunity

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Science Signaling  03 Jul 2012:
Vol. 5, Issue 231, pp. ec181
DOI: 10.1126/scisignal.2003360

Regulatory T cells (Tregs) are a greater fraction of total CD4+ T cells in visceral adipose tissue (VAT) than in spleen or lymphoid tissues, and these VAT-resident Tregs have a distinct gene expression profile. VAT-resident Tregs cells control the inflammatory state and insulin sensitivity of adipose tissue. Cipolletta et al. compared the gene expression profiles of mouse Tregs from VAT and lymph node and found a larger abundance of transcripts of the genes encoding the nuclear receptor PPAR-γ in VAT-resident Tregs. Retroviral transduction of Foxp3 in combination with Pparg into naïve CD4+ T cells resulted in increased expression of genes characteristic of VAT Tregs. Addition of the synthetic PPAR-γ agonist pioglitazone to naïve CD4+ T cells transduced with Foxp3 alone or in combination with Pparg resulted in increased expression of a set of lipid metabolism genes. PPAR-γ isoforms coimmunoprecipitated with Foxp3 in human embryonic kidney (HEK) 293 cells. The authors explored the importance of PPAR-γ in vivo by constructing transgenic mice in which Pparg was selectively knocked out in Tregs (Treg-PParg-mut). Mutant mice had fewer VAT Tregs than did wild-type mice. Comparing gene expression profiles of VAT Tregs from mutant and wild-type mice showed a decreased expression of genes characteristic of VAT Tregs in the mutant cells. In obese mice, addition of pioglitazone increased the number of Tregs in epididymal but not subcutaneous, perirenal, or liver adipose tissue and shifted their gene expression profiles toward that typical of VAT Tregs. Because pioglitazone is a known insulin-sensitizing agent, the authors examined insulin resistance and glucose tolerance in obese Treg-PParg-mut and wild-type mice treated with pioglitazone. Treatment with pioglitazone was more effective at decreasing insulin resistance and increasing glucose tolerance in obese wild-type mice than in obese Treg-PParg-mut mice. PPAR-γ thus functions within Tregs in adipose tissue to enhance insulin sensitivity.

D. Cipolletta, M. Feuerer, A. Li, N. Kamei, J. Lee, S. E. Shoelson, C. Benoist, D. Mathis, PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012). [PubMed]