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Paper Reading 01 Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ  ChangLiu ,MariaChikina, Rahul Deshpande et al Immunity（June 2019） Regulatory T (Treg) cells are crucial for immune homeostasis, but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME), the mechanisms by which they exert this effect have not been fully elucidated. TAM shave been categorized into two functionally distinct sub-types, anti-tumor, pro-inflammatory M1-like TAMs and pro-tumor, anti-inflammatory M2-like TAMs.M1-like TAM activation is induced by proinflammatory signals, such as interferon-g (IFNg) and lipopolysaccharide (LPS), and is coupled to anabolic metabolism, including aerobic glycolysis and fatty acid synthesis. In contrast, M2-like TAM activation is driven by anti-inflammatory cytokines, such as interleukin-4 (IL-4) and IL-10, and catabolic metabolism, including oxidative phosphorylation and fatty acid oxidation (FAO). Treg cells suppressed CD8+ T cell secretion of interferon-g (IFNg), which would otherwise block the activation of Sterol regulatory element-binding protein1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Firstly, Liu et al analyzed the composition of intratumoral CD45 +cellsfrom Foxp3 Cre-YFP or Nrp1 L/L Foxp3 Cre-YFP mice inoculated with B16 to gain atemporal profile of the cellular changes within the TME during tumor progression and how this is impacted by Treg cells, the composition of the immune infiltrations in the TME of Nrp1 L/L Foxp3 Cre-YFP mice was higher percentages of CTLs, NKs and CD4 +Teff cells and lower percentages of monocytes and TAMs. the results reveal that intratumoral Treg cells maintain their immunosuppressive effects on multiple cell types, particularly M2-like TAMs that, in turn, increase their tumor occupancy (cell density)and enhance their pro-tumor metabolic function. Then they performed globally transcriptomic analysis (Affymetrix array) of purified tumor-infiltrating CD45+ cells from Nrp1 L/LFoxp3 Cre-YFPand Foxp3 Cre-YFP mice over time (D8/D6, D12, D18) in both the B16 and MC38 tumor models. They found that genes involved in lipid metabolism, such as targets of the transcription factor sterol regulatory element-binding protein 1 (SREBP1) were enriched. It suggested that Treg cells may regulate TAMsby modulating their metabolism via the SREBP1 pathway. High-dimensional flow cytometry analysis shows that functional Treg cells are required for theM2-like cell fate determination of TAMs depletion of CD8+ T cells in B16-bearing Nrp1 L/L Foxp3 Cre-YFPmice completely restored the number and phenotype of M2-like TAMs with concomitantly restored tumor growth, without affecting the M1-like TAM compartment. IFNγ neutralization secreted by CD8 + T cell impact M2-like TAM lipid storage intratumoral Treg cells promotes M2-like TAMs indirectly by limiting IFN γ production by CD8 + T cells. SREBP1 activation promotes de novo fatty acid synthesis upon high energy demands in rapidly proliferating cells, the activation of SREBP1 pathway was disrupted in TAMs. Blunting the suppressive capacity of intratumoral Treg cells unleashes anti-tumor CD8 +T cells that cause enhanced AMPK activation in TAMs and impaired SREBP1 upregulation, which in turn selectively impedes M2-like TAM survival and their tumor-promoting activity. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy. https:///10.1016/j.immuni.2019.06.017 02 Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt+ Regulatory T Cells and Exacerbate Colitis in Mice  Graham J. Britton, Eduardo J. Contijoch , Ilaria Mogno et al Immunity（January2019） It is widely proposed that IBD occurs as the result of a dysregulated immune response to microbiota and individual susceptibility is determined by both host genetics and the composition of the gut microbiota. Among the cells most highly induced upon gut microbiota colonization in ex-germ-free mice are RORγt+ FoxP3− Th17 cells and FoxP3+regulatory T (Treg) cells. The majority of gut Th17 cells are specific for microbial antigens. They colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germfree mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt + Treg cells. Then they used flow cytometry to examine the relative induction of Treg cell subsets by healthy and IBD donor microbiotas and observed a significant expansion of RORγt + Treg cells induced by healthy microbiotas relative to IBD microbiotas in both colon and ileum. Transfer of CD45RBhi (naive) CD4 + T cells to Rag1-/-mice induces colitis-like pathology, but only in the presence of an immunogenic microbiota. Colonic RORγt+ Treg cells from mice colonized with either healthy or IBD microbiotas secreted minimal IL-17A when stimulated ex vivo compared to FoxP3− RORγt+ Th cells. Colitis was more severe in mice colonized with fecal microbiotas from individuals with IBD than those colonized with microbiotas from healthy donors. They observed in unchallenged gnotobiotic B6mice correlated with colitis severity in RagTCT mice colonized with the same donor microbiotas. A total of 15 healthy and 14 IBD microbiotas were tested in both models. The proportion of colon and ileumRORγt + Th cells induced by microbiota in B6 mice was positively correlated with colitis severity in RagTCT mice colonized with the same microbiota while the induction of RORγt + Treg cells in B6 mice was inversely correlated with colitis severity in RagTCT mice. The proportions of Th17 and RORγt + Treg cells induced by each microbiota were predictive of human disease states and accounted for disease severity in the Rag1-/-colitis model. Their findings define an impact on intestinal Th17 and RORγt+ regulatory T cell compartments as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis. https:///10.1016/j.immuni.2018.12.015 END |
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