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Dietary Fat Inflames CD4 + T Cell Memory in Obesity

2017; Cell Press; Volume: 25; Issue: 3 Linguagem: Inglês

10.1016/j.cmet.2017.02.012

1932-7420

Nicole M. Chapman, Hongbo Chi,

Immune Cell Function and Interaction

T cells promote inflammation in obesity, but how metabolic stress associated with obesity alters T cell responses remains unclear. In this issue of Cell Metabolism, Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar demonstrate that saturated fatty acids directly increase effector-memory T cell formation by amplifying T cell antigen-receptor-induced PI3K/Akt signaling. T cells promote inflammation in obesity, but how metabolic stress associated with obesity alters T cell responses remains unclear. In this issue of Cell Metabolism, Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar demonstrate that saturated fatty acids directly increase effector-memory T cell formation by amplifying T cell antigen-receptor-induced PI3K/Akt signaling. Obesity is a growing healthcare epidemic affecting over 30% of adults in the United States alone. The complex interplay of genetics and metabolic dysregulation underpins the onset and severity of obesity. Further, cellular and soluble mediators of the immune system drive chronic, low-grade inflammation in obesity. Consequently, disorders such as type 2 diabetes and cardiovascular disease can develop, while immune responses against infectious agents and cancers are diminished (Gerriets and MacIver, 2014Gerriets V.A. MacIver N.J. Front. Immunol. 2014; 5: 379Crossref PubMed Scopus (97) Google Scholar). The front-line defenses for combating obesity are limiting dietary nutrient intake and increasing energy expenditure through exercise. How changes in energy or nutrient homeostasis contribute to the immune cell dysfunction that drives obesity-associated inflammation is unknown. In this issue of Cell Metabolism, Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar show that saturated fatty acids (SFAs) increase T cell antigen receptor (TCR) clustering and signaling through the PI3K/Akt axis and fuel fatty acid oxidation (FAO) in metabolically stressed environments. These processes drive the differentiation of CD4+ effector-memory (TEM) cells that traffic into non-lymphoid and inflamed tissues (Figure 1). Among immune cells, T cells promote obesity-associated inflammation via their cytotoxic activities and by secreting cytokines (Gerriets and MacIver, 2014Gerriets V.A. MacIver N.J. Front. Immunol. 2014; 5: 379Crossref PubMed Scopus (97) Google Scholar). T cells are activated when the TCR binds its cognate peptide-major histocompatibility complex (MHC) molecule, which is presented by dendritic cells (DCs). Co-stimulatory and cytokine receptor signals also direct T cell differentiation into effector T cell subsets and memory T (TM) cells, which are divided into TEM cells, central-memory T (TCM) cells, and tissue-resident memory T (TRM) cells (Mueller and Mackay, 2016Mueller S.N. Mackay L.K. Nat. Rev. Immunol. 2016; 16: 79-89Crossref PubMed Scopus (590) Google Scholar). Upon migrating into adipose tissue, activated T cells cause adipocytes to release additional inflammatory mediators, further exacerbating inflammation. Activated T cells that migrate into other tissues also play deleterious roles in obesity-related diseases like atherosclerosis (Gerriets and MacIver, 2014Gerriets V.A. MacIver N.J. Front. Immunol. 2014; 5: 379Crossref PubMed Scopus (97) Google Scholar). Because TM cells are long-lived and rapidly re-acquire effector functions upon antigen re-stimulation (Mueller and Mackay, 2016Mueller S.N. Mackay L.K. Nat. Rev. Immunol. 2016; 16: 79-89Crossref PubMed Scopus (590) Google Scholar), characterizing how metabolic stress influences TM cell responses could help resolve the mechanisms underlying obesity-associated diseases. To address whether metabolic stress that promotes obesity also alters TM cell responses, Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar analyzed CD4+ TM cells in mice fed a conventional diet (CD) or a high-fat diet (HFD). They found that TM cells isolated from CD-fed hosts display features of TCM cells and migrate into mesenteric lymph nodes. By contrast, TM cells isolated from HFD-fed mice traffic into non-lymphoid tissues and inflammatory sites regardless of the metabolic status of the host, suggesting that HFD-derived nutrients intrinsically promote the TEM cell program. The differential trafficking patterns are caused by changes in the expression of chemokine receptors and adhesion molecules, including CXCR3, CCR7, and CD62L. Obese humans also accumulate CXCR3+ TEM-like cells, suggesting that metabolic stress heightens TEM cell differentiation and promotes the trafficking of those cells into tissues and sites of inflammation during obesity. Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar next asked how metabolic stress increases TEM cell differentiation. Although HFD-exposed DCs induce less T cell proliferation, DC-dependent mechanisms do not potentiate TEM cell differentiation within the HFD environment. Instead, exposure to the SFA palmitate was shown to directly increase TEM cell differentiation by augmenting T cell membrane fluidity, TCR clustering, and TCR-inducible PI3K/Akt signaling. Indeed, T cells activated in the presence of an Akt activator are phenotypically similar to TEM cells. Further, genetic or pharmacological inhibition of the PI3K p110δ catalytic subunit limits TEM cell differentiation and CXCR3-dependent trafficking. These results are consistent with the role of PI3K/Akt-mediated Foxo1 inactivation, which subsequently inhibits TCM cell differentiation and lymphoid tissue homing (Kim et al., 2013Kim M.V. Ouyang W. Liao W. Zhang M.Q. Li M.O. Immunity. 2013; 39: 286-297Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). Of note, TCR-inducible Akt activation, for unknown reasons, is more tightly coupled to PI3K p110δ function during metabolic stress. TM cells from the HFD environment also induce skin allograft rejection more efficiently than do CD-derived TM cells (Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar), suggesting that SFAs like palmitate modulate TCR-dependent responses in TM cells. Further work could dissect how CXCR3 expression is induced on TM cells within the HFD environment; one candidate is the mTORC1-Tbet axis (Rao et al., 2010Rao R.R. Li Q. Odunsi K. Shrikant P.A. Immunity. 2010; 32: 67-78Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar), although TCR-inducible mTORC1 activation is not further activated by HFD (Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Additional studies could also clarify the upstream events driving augmented PI3K/Akt signaling. Changes in protein lipidation could activate proteins upstream of PI3K/Akt to influence TEM cell differentiation. For instance, the kinase Lck initiates TCR signaling events, and its activation is tuned by protein palmitoylation (Akimzhanov and Boehning, 2015Akimzhanov A.M. Boehning D. Proc. Natl. Acad. Sci. USA. 2015; 112: 11876-11880Crossref PubMed Scopus (56) Google Scholar). Therefore, a combined increase in TCR clustering and Lck activation might render HFD-derived TEM cells more sensitive to secondary TCR signals in tissues or inflammatory sites. The authors also showed that FAO of palmitate promotes TEM cell differentiation, potentially by providing ATP to support TM cell survival (Buck et al., 2015Buck M.D. O'Sullivan D. Pearce E.L. J. Exp. Med. 2015; 212: 1345-1360Crossref PubMed Scopus (708) Google Scholar). How is FAO engaged during HFD-induced metabolic stress? Previous studies demonstrate that lipolysis and oxidation of de-novo-synthesized fatty acids promote TM cell differentiation (Buck et al., 2015Buck M.D. O'Sullivan D. Pearce E.L. J. Exp. Med. 2015; 212: 1345-1360Crossref PubMed Scopus (708) Google Scholar). Further, inhibition of either mTORC1 or mTORC2 activity boosts TM cell differentiation in lean mice (Buck et al., 2015Buck M.D. O'Sullivan D. Pearce E.L. J. Exp. Med. 2015; 212: 1345-1360Crossref PubMed Scopus (708) Google Scholar, Pollizzi et al., 2015Pollizzi K.N. Patel C.H. Sun I.H. Oh M.H. Waickman A.T. Wen J. Delgoffe G.M. Powell J.D. J. Clin. Invest. 2015; 125: 2090-2108Crossref PubMed Scopus (258) Google Scholar, Rao et al., 2010Rao R.R. Li Q. Odunsi K. Shrikant P.A. Immunity. 2010; 32: 67-78Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar). Thus, mTOR signaling appears to antagonize FAO. Interestingly, the data presented by Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar suggest that mTORC2, but not mTORC1, activity is enhanced in T cells exposed to SFAs, so discrete signaling pathways might regulate FAO of different sources or types of fatty acids. Future work can also explore the requirement for AMPK in promoting FAO in T cells from obese environments. Indeed, AMPK promotes TM cell differentiation in lean environments and mediates palmitate-dependent NLRP3-ASC inflammasome activation in macrophages, which also trigger inflammation in obesity (Buck et al., 2015Buck M.D. O'Sullivan D. Pearce E.L. J. Exp. Med. 2015; 212: 1345-1360Crossref PubMed Scopus (708) Google Scholar, Wen et al., 2011Wen H. Gris D. Lei Y. Jha S. Zhang L. Huang M.T. Brickey W.J. Ting J.P. Nat. Immunol. 2011; 12: 408-415Crossref PubMed Scopus (1272) Google Scholar). In sum, Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar demonstrate that HFDs drive dysregulated TEM cell responses by modulating the PI3K/Akt axis and inducing metabolic reprogramming via FAO. As pro-inflammatory macrophage activation is also triggered by SFAs (Saberi et al., 2009Saberi M. Woods N.B. de Luca C. Schenk S. Lu J.C. Bandyopadhyay G. Verma I.M. Olefsky J.M. Cell Metab. 2009; 10: 419-429Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, Wen et al., 2011Wen H. Gris D. Lei Y. Jha S. Zhang L. Huang M.T. Brickey W.J. Ting J.P. Nat. Immunol. 2011; 12: 408-415Crossref PubMed Scopus (1272) Google Scholar), understanding how SFA-induced T cell and macrophage activation cooperates to promote obesity-related diseases may aid the development of new therapies for these diseases. Because Mauro et al., 2017Mauro C. Smith J. Cucchi D. Coe D. Fu H. Bonacina F. Baragetti A. Cermenati G. Caruso D. Mitro N. et al.Cell Metab. 2017; 25 (this issue): 593-609Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar also found that obesity enhances TEM cell differentiation at the expense of the naive T cell pool, it will be interesting to further characterize how medical perturbations of the immune system (e.g., vaccinations and immunotherapy) are affected during metabolic stress and if such responses are altered by restricting SFAs or other nutrients in obese individuals. These studies might help boost immunity against pathogens and tumors in obese patients. Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated SignalsMauro et al.Cell MetabolismFebruary 9, 2017In BriefLymphocyte infiltration of non-lymphoid tissues, including adipose and vascular tissues, is a prominent feature of chronic inflammation in diet obesity. Mauro et al. find that the saturated fatty-acid palmitate activates a PI3K p110δ-Akt pathway leading to CD4+ T cell differentiation into effector memory-like T cells upon priming in obese mice and humans. Full-Text PDF Open Access