Regulatory T Cells Expressing PPAR-γ Control Inflammation in Obesity

A recent study (Cipolletta et al., 2012Cipolletta D. Feuerer M. Li A. Kamei N. Lee J. Shoelson S.E. Benoist C. Mathis D. Nature. 2012; (in press. Published online: May 16, 2012)https://doi.org/10.1038/nature11132Crossref PubMed Scopus (809) Google Scholar) shows that regulatory T (Treg) cells expressing the peroxisome-proliferator- activated receptor (PPAR-γ) are engaged in suppressing adipose tissue inflammation in obesity, suggesting that Treg cells may be a target for treatment and prevention of adipose tissue inflammation and insulin resistance. A recent study (Cipolletta et al., 2012Cipolletta D. Feuerer M. Li A. Kamei N. Lee J. Shoelson S.E. Benoist C. Mathis D. Nature. 2012; (in press. Published online: May 16, 2012)https://doi.org/10.1038/nature11132Crossref PubMed Scopus (809) Google Scholar) shows that regulatory T (Treg) cells expressing the peroxisome-proliferator- activated receptor (PPAR-γ) are engaged in suppressing adipose tissue inflammation in obesity, suggesting that Treg cells may be a target for treatment and prevention of adipose tissue inflammation and insulin resistance. In obesity, enlarged adipocytes accumulating in visceral adipose tissue (VAT) elicit infiltration of macrophages and other immune cells (Feuerer et al., 2009Feuerer M. Herrero L. Cipolletta D. Naaz A. Wong J. Nayer A. Lee J. Goldfine A.B. Benoist C. Shoelson S. et al.Nat. Med. 2009; 15: 930-939Crossref PubMed Scopus (1513) Google Scholar, Winer et al., 2009Winer S. Chan Y. Paltser G. Truong D. Tsui H. Bahrami J. Dorfman R. Wang Y. Zielenski J. Mastronardi F. et al.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (1042) Google Scholar, Nishimura et al., 2009Nishimura S. Manabe I. Nagasaki M. Eto K. Yamashita H. Ohsugi M. Otsu M. Hara K. Ueki K. Sugiura S. et al.Nat. Med. 2009; 15: 914-920Crossref PubMed Scopus (1611) Google Scholar, Olefsky and Glass, 2010Olefsky J.M. Glass C.K. Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar). These cells secrete proinflammatory cytokines and mediate chronic low-grade inflammation in VAT. The inflamed adipose tissue, in turn, may release cytokines, adipokines, fatty acids, and other substances that may affect other organs, such as liver and muscle, leading to systemic insulin resistance. A recent study from Cipolletta and colleagues reveals an important role for VAT-specific natural Treg cells in the suppression of obesity-associated inflammation in VAT and consequently in combatting insulin resistance (Cipolletta et al., 2012Cipolletta D. Feuerer M. Li A. Kamei N. Lee J. Shoelson S.E. Benoist C. Mathis D. Nature. 2012; (in press. Published online: May 16, 2012)https://doi.org/10.1038/nature11132Crossref PubMed Scopus (809) Google Scholar). Naturally occurring Treg cells are a unique CD4+ T cell subpopulation specifically adapted to the suppression of aberrant or excessive immune responses that are harmful to the host (Sakaguchi et al., 2008Sakaguchi S. Yamaguchi T. Nomura T. Ono M. Cell. 2008; 133: 775-787Abstract Full Text Full Text PDF PubMed Scopus (3681) Google Scholar). In physiological conditions, they constitute ∼10% of peripheral CD4+ T cells and are characterized by the expression of the transcription factor Foxp3. The majority of Foxp3+ CD4+ Treg cells are produced by the thymus as a functionally mature and distinct T cell subpopulation, although naive conventional T cells can also differentiate into Foxp3+ Treg cells under certain conditions. The key role of Foxp3+ Treg cells in immune tolerance and homeostasis is best illustrated by Foxp3 gene mutations, which cause Treg cell deficiency or dysfunction, consequently inducing severe autoimmune diseases such as type 1 diabetes mellitus, allergy, and inflammatory bowel disease in humans (Sakaguchi et al., 2008Sakaguchi S. Yamaguchi T. Nomura T. Ono M. Cell. 2008; 133: 775-787Abstract Full Text Full Text PDF PubMed Scopus (3681) Google Scholar). Foxp3+ Treg cells are involved in suppressive control of almost any physiological and pathological immune response and inflammation at any site. Indeed, they exhibit suppressive activity in an inflammation type-dependent manner, controlling specific types of T cells, such as Th1, Th2, and Th17 (Josefowicz et al., 2012Josefowicz S.Z. Lu L.-F. Rudensky A.Y. Annu. Rev. Immunol. 2012; 30: 531-564Crossref PubMed Scopus (1961) Google Scholar) (Figure 1). Foxp3+ Treg cells are abundant in VAT and have a different T cell receptor repertoire compared with Treg cells in other tissues, suggesting that they might be activated via the recognition of a fat tissue-specific antigen (Feuerer et al., 2009Feuerer M. Herrero L. Cipolletta D. Naaz A. Wong J. Nayer A. Lee J. Goldfine A.B. Benoist C. Shoelson S. et al.Nat. Med. 2009; 15: 930-939Crossref PubMed Scopus (1513) Google Scholar). The number of VAT Treg cells is strikingly and specifically reduced in insulin-resistant models of obesity, and their expansion improves insulin sensitivity. Cipolletta and colleagues show that these VAT-resident Foxp3+ Tregs specifically express the peroxisome proliferator-activated receptor (PPAR)γ (Cipolletta et al., 2012Cipolletta D. Feuerer M. Li A. Kamei N. Lee J. Shoelson S.E. Benoist C. Mathis D. Nature. 2012; (in press. Published online: May 16, 2012)https://doi.org/10.1038/nature11132Crossref PubMed Scopus (809) Google Scholar), a nuclear receptor that is required for adipocyte development and is also the target for the insulin-sensitizing drugs thiazolidinediones (TZDs) (Spiegelman, 1998Spiegelman B.M. Diabetes. 1998; 47: 507-514Crossref PubMed Scopus (1640) Google Scholar). PPARγ appears to interact with Foxp3 in VAT-Treg cells. Indeed, ectopic coexpression of Foxp3 and PPARγ in conventional T cells induces a VAT-Treg type gene-expression profile. Specifically, two variants of PPARγ, PPARγ1 and 2, both promote upregulation of VAT-Treg genes, but only PPARγ1 induces repression of VAT-Treg genes. Cipolletta et al., 2012Cipolletta D. Feuerer M. Li A. Kamei N. Lee J. Shoelson S.E. Benoist C. Mathis D. Nature. 2012; (in press. Published online: May 16, 2012)https://doi.org/10.1038/nature11132Crossref PubMed Scopus (809) Google Scholar further investigate the role of PPARγ expression in VAT-Treg by the use of Foxp3-dependent PPARγconditional knockout mice. This Treg cell-specific deletion of PPARγ reduces the number of Treg cells specifically in VAT, resulting in an increase in VAT infiltration by proinflammatory macrophages and monocytes. Interestingly, PPARγ stimulation by pioglitazone, a TZD drug, specifically increases Treg cell numbers in the VAT of obese mice fed a high-fat diet, leading to a concomitant improvement in insulin sensitivity. These results collectively indicate that PPARγ-expressing Foxp3+ Treg cells play a unique role in suppressing VAT inflammation caused by overnutrition, and that TZDs may enhance insulin sensitivity, at least in part, through increasing PPARγ-expressing Foxp3+ Treg cells in VAT. These findings on VAT-resident PPARγ-expressing Treg cells raise several key issues for future research. First, what is the role of PPARγ for VAT Treg cell function? Given that PPARγ is regulated by free fatty acids and their metabolites (Chawla et al., 2001Chawla A. Repa J.J. Evans R.M. Mangelsdorf D.J. Science. 2001; 294: 1866-1870Crossref PubMed Scopus (1685) Google Scholar), Treg cells may sense these substances, as a result, express PPARγ and migrate to the adipose tissue releasing the substances. Alternatively, it is also possible that Treg cells recruited to VAT inflammation sites via chemokine or the recognition of a tissue-specific antigen may express PPARγ in response to local signals. PPARγ is also expressed by macrophages as a negative regulator of intracellular macrophage inflammatory pathways, possibly resulting in their conversion from M1 macrophages, which are proinflammatory, to the anti-inflammatory M2 type (Olefsky and Glass, 2010Olefsky J.M. Glass C.K. Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar). Thus, PPARγ-expressing Treg cells and macrophages might cooperatively contribute to suppressing obesity-associated VAT inflammation. TZDs may act on both Treg cells and macrophages, restoring insulin sensitivity. Second, how do the Treg cells control inflammation in VAT? They secrete a high amount of IL-10, an anti-inflammatory cytokine, as observed with Foxp3 Treg cells in the intestinal mucosa, where Treg cells appear to be continually activated by intestinal commensal bacteria. It remains to be determined whether Foxp3+ Treg cells primarily control effector T cells (Winer et al., 2009Winer S. Chan Y. Paltser G. Truong D. Tsui H. Bahrami J. Dorfman R. Wang Y. Zielenski J. Mastronardi F. et al.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (1042) Google Scholar; Nishimura et al., 2009Nishimura S. Manabe I. Nagasaki M. Eto K. Yamashita H. Ohsugi M. Otsu M. Hara K. Ueki K. Sugiura S. et al.Nat. Med. 2009; 15: 914-920Crossref PubMed Scopus (1611) Google Scholar), which then activate macrophages, or directly control macrophages, at least in part via secretion of IL-10. Augmentation of such suppressive activities of PPARγ-expressing Treg cells may enable better control of VAT inflammation in obesity. Lastly, are Treg cells involved in other chronic low-grade inflammation accompanying tissue damage? In atherosclerosis, for example, Foxp3+ Treg cells present in atheroma lesions have been implicated in suppressing the formation of foam cells from macrophages (Ait-Oufella et al., 2006Ait-Oufella H. Salomon B.L. Potteaux S. Robertson A.-K.L. Gourdy P. Zoll J. Merval R. Esposito B. Cohen J.L. Fisson S. et al.Nat. Med. 2006; 12: 178-180Crossref PubMed Scopus (816) Google Scholar). Pioglitazone has a protective effect on atherosclerosis. The effect of pioglitazone in VAT, causing an increase in VAT Treg cells, suggests that a similar mechanism may underlie the protective effects of the drug in atherosclerosis. Further investigation is required to determine the possible contribution of Foxp3+ Treg cells to the control of other chronic immunometabolic diseases, in which targeting tissue-specific Foxp3+ Treg cells could represent a new approach for treatment and prevention. In conclusion, the finding by Cipolletta et al., 2012Cipolletta D. Feuerer M. Li A. Kamei N. Lee J. Shoelson S.E. Benoist C. Mathis D. Nature. 2012; (in press. Published online: May 16, 2012)https://doi.org/10.1038/nature11132Crossref PubMed Scopus (809) Google Scholar on the presence of VAT-resident PPARγ-expressing Treg cells that control VAT inflammation in obesity provides a new link between immunoregulation and metabolic disease, and may be exploited to devise immunotherapies for immunometabolic diseases.