Adipose tissue invariant natural killer T (iNKT) cells are phenotypically different from other iNKT cells because they produce IL-10 and control metabolic homeostasis. Why that is the case is ...unclear. Here, using single-cell RNA sequencing, we found several adipose iNKT clusters, which we grouped into two functional populations based on NK1.1 expression. NK1.1NEG cells almost exclusively produced IL-10 and other regulatory cytokines, while NK1.1POS iNKT cells predominantly produced IFNγ. Mechanistically, biochemical fractionation revealed that free fatty acids drive IL-10 production primarily in NK1.1NEG iNKT cells via the IRE1α-XBP1s arm of the unfolded protein response. Correspondingly, adoptive transfer of adipose tissue NK1.1NEG iNKT cells selectively restored metabolic function in obese mice. Further, we found an unexpected role for NK1.1POS iNKT cells in lean adipose tissue, as IFNγ licenses natural killer cell-mediated macrophage killing to limit pathological macrophage expansion. Together, these two iNKT cell populations utilize non-redundant pathways to preserve metabolic integrity.
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•scRNA-seq reveals distinct populations of adipose tissue iNKT cells•FFAs drive IL-10 production via IRE1α-XBP1s signaling, primarily in NK1.1NEG iNKT cells•NK1.1NEG regulatory iNKT cells selectively restore metabolic function during obesity•In lean adipose, NK1.1POS iNKT cells license NK cell killing of macrophages via IFNγ
LaMarche et al. reveal two pathways by which iNKT cell subsets control adipose tissue inflammation. NK1.1NEG iNKT cells dominantly produce anti-inflammatory IL-10, driven by intracellular lipid accumulation and IRE1α-XBP1s signaling. In contrast, NK1.1POS cells produce IFNγ, which, in lean adipose tissue, drives NK cell-mediated macrophage killing to limit pathogenic macrophage expansion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • Immunometabolism can be split into two main themes: whole-body metabolism and cellular bioenergetics. • Adipose tissue is a prime example to illustrate immunometabolism as a whole. • ...Immune cells resident in adipose tissue produce metabolism-altering molecules. • Cell intrinsic metabolism dictates immune cell function, which in turn can alter systemic metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
3.
Innate T Cells Govern Adipose Tissue Biology LaMarche, Nelson M; Kohlgruber, Ayano C; Brenner, Michael B
The Journal of immunology (1950),
10/2018, Volume:
201, Issue:
7
Journal Article
Peer reviewed
Open access
During the past 25 y, the immune system has appeared as a key regulator of adipose tissue biology and metabolic homeostasis. In lean animals, adipose-resident leukocytes maintain an anti-inflammatory ...microenvironment that preserves the proper functioning of the tissue. In this review, we describe two populations of innate T cells enriched in adipose tissue, invariant NKT and γδ T cells, and how they serve overlapping and nonredundant roles in controlling adipose tissue functions. These cells interact with and expand anti-inflammatory regulatory T cells and M2 macrophages, thereby driving a metabolically beneficial tissue milieu. Surprisingly, we have found that adipose invariant NKT and γδ T cells also promote weight loss and heat production in a process called "nonshivering thermogenesis." The data surrounding these two cell types highlight their powerful ability to regulate not only other leukocytes, but also tissue-wide processes that affect an entire organism.
In this issue of Cell Metabolism, Macdougall et al. (2018) identify two subsets of conventional dendritic cells in visceral adipose tissue and demonstrate that these subsets engage distinct ...adipocyte-associated signaling pathways to drive their tolerogenic phenotypes in the lean state.
In this issue of Cell Metabolism, Macdougall et al. identify two subsets of conventional dendritic cells in visceral adipose tissue and demonstrate that these subsets engage distinct adipocyte-associated signaling pathways to drive their tolerogenic phenotypes in the lean state.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human ...lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2
mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2
mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Eosinophils are critical cellular mediators in allergic asthma and inflammation; however, the signals that regulate their functions are unclear. The transcription factor STAT6 regulates Th2 cytokine ...responses, acting downstream of IL-4 and IL-13. We showed previously that eosinophil-derived IL-13 plays an important role in the recruitment of T cells to the lung and the subsequent development of allergic asthma. However, whether eosinophils respond to Th2 signals to control allergic airway inflammation is unclear. In this report, we show that STAT6(-/-) eosinophils are unable to induce the development of allergic lung inflammation, including recruitment of CD4(+) T cells, mucus production, and development of airways hyperresponsiveness. This is likely due to the reduced migration of STAT6(-/-) eosinophils to the lung and in response to eotaxin. These data indicate that, like Th cells, eosinophils need to respond to Th2 cytokines via STAT6 during the development of allergic airway inflammation.
Innate T cells, including CD1d-restricted invariant natural killer T (iNKT) cells, are characterized by their rapid activation in response to non-peptide antigens, such as lipids. While the ...transcriptional profiles of naive, effector, and memory adaptive T cells have been well studied, less is known about the transcriptional regulation of different iNKT cell activation states. Here, using single-cell RNA-sequencing, we performed longitudinal profiling of activated murine iNKT cells, generating a transcriptomic atlas of iNKT cell activation states. We found that transcriptional signatures of activation are highly conserved among heterogeneous iNKT cell populations, including NKT1, NKT2, and NKT17 subsets, and human iNKT cells. Strikingly, we found that regulatory iNKT cells, such as adipose iNKT cells, undergo blunted activation and display constitutive enrichment of memory-like cMAF
and KLRG1
populations. Moreover, we identify a conserved cMAF-associated transcriptional network among NKT10 cells, providing novel insights into the biology of regulatory and antigen-experienced iNKT cells.
Myeloid cells are known to suppress antitumour immunity
. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of ...human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab
given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Invariant natural killer T (iNKT) cells are a specialized T cell subset that plays an important role in host defense, orchestrating both innate and adaptive immune effector responses against a ...variety of microbes. Specific microbial lipids and mammalian self lipids displayed by the antigen-presenting molecule CD1d can activate iNKT cells through their semi-invariant αβ T cell receptors (TCRs). iNKT cells also constitutively express receptors for inflammatory cytokines typically secreted by antigen-presenting cells (APCs) after recognition of pathogen-associated molecular patterns (PAMPs), and they can be activated through these cytokine receptors either in combination with TCR signals, or in some cases even in the absence of TCR signaling. During infection, experimental evidence suggests that both TCR-driven and cytokine-driven mechanisms contribute to iNKT cell activation. While the relative contributions of these two signaling mechanisms can vary widely depending on the infectious context, both lipid antigens and PAMPs mediate reciprocal activation of iNKT cells and APCs, leading to downstream activation of multiple other immune cell types to promote pathogen clearance. In this review, we discuss the mechanisms involved in iNKT cell activation during infection, focusing on the central contributions of both lipid antigens and PAMP-induced inflammatory cytokines, and highlight in vivo examples of activation during bacterial, viral, and fungal infections.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Tissue‐resident iNKT cells maintain tissue homeostasis and peripheral surveillance against pathogens; however, studying these cells is challenging due to their low abundance and poor recovery from ...tissues. We here show that iNKT transnuclear mice, generated by somatic cell nuclear transfer, have increased tissue resident iNKT cells. We examined expression of PLZF, T‐bet, and RORγt, as well as cytokine/chemokine profiles, and found that both monoclonal and polyclonal iNKT cells differentiated into functional subsets that faithfully replicated those seen in wild‐type mice. We detected iNKT cells from tissues in which they are rare, including adipose, lung, skin‐draining lymph nodes, and a previously undescribed population in Peyer's patches (PP). PP‐NKT cells produce the majority of the IL‐4 in Peyer's patches and provide indirect help for B‐cell class switching to IgG1 in both transnuclear and wild‐type mice. Oral vaccination with α‐galactosylceramide shows enhanced fecal IgG1 titers in iNKT cell‐sufficient mice. Transcriptional profiling reveals a unique signature of PP‐NKT cells, characterized by tissue residency. We thus define PP‐NKT as potentially important for surveillance for mucosal pathogens.
Synopsis
We used iNKT transnuclear mice to detect iNKT cells from tissues where they are rare, including adipose, lung, skin‐draining lymph nodes, and a previously undescribed population in Peyer's patches that produces IL‐4 and helps B‐cell class switching to IgG1.
iNKT transnuclear mice faithfully model tissue‐resident iNKT cell populations.
iNKT cells are found in Peyer's patches of both wild type and transnuclear mice and can be used as cellular adjuvants for oral vaccination.
PP‐NKT cells produce the majority of the IL‐4 in Peyer's patches, and provide indirect help for B‐cell class switching to IgG1.
A novel population of iNKT cells with a unique function in supporting IgG1 class switching in the gut mucosa may be important for surveillance for mucosal pathogens.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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