Immunology A Linchpin for Metabolism and Immunity

Ernesto Andrianantoandro

Science Signaling, AAAS, Washington, DC 20005, USA

Regulatory T cells (T_regs) are a greater fraction of total CD4⁺ T cells in visceral adipose tissue (VAT) than in spleen or lymphoid tissues, and these VAT-resident T_regs have a distinct gene expression profile. VAT-resident T_regs cells control the inflammatory state and insulin sensitivity of adipose tissue. Cipolletta et al. compared the gene expression profiles of mouse T_regs from VAT and lymph node and found a larger abundance of transcripts of the genes encoding the nuclear receptor PPAR- in VAT-resident T_regs. Retroviral transduction of Foxp3 in combination with Pparg into naïve CD4⁺ T cells resulted in increased expression of genes characteristic of VAT T_regs. Addition of the synthetic PPAR- 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- isoforms coimmunoprecipitated with Foxp3 in human embryonic kidney (HEK) 293 cells. The authors explored the importance of PPAR- in vivo by constructing transgenic mice in which Pparg was selectively knocked out in T_regs (T_reg-PParg-mut). Mutant mice had fewer VAT T_regs than did wild-type mice. Comparing gene expression profiles of VAT T_regs from mutant and wild-type mice showed a decreased expression of genes characteristic of VAT T_regs in the mutant cells. In obese mice, addition of pioglitazone increased the number of T_regs in epididymal but not subcutaneous, perirenal, or liver adipose tissue and shifted their gene expression profiles toward that typical of VAT T_regs. Because pioglitazone is a known insulin-sensitizing agent, the authors examined insulin resistance and glucose tolerance in obese T_reg-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 T_reg-PParg-mut mice. PPAR- thus functions within T_regs 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- is a major driver of the accumulation and phenotype of adipose tissue T_reg cells. Nature 486, 549–553 (2012). [PubMed]

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