Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Layman, Awo Akosua Kesewa; Deng, Guoping; O’Leary, Claire E.; Tadros, Samuel; Thomas, Robin; Dybas, Joseph M.; Moser, Emily K.; Wells, Andrew D.; Doliba, Nicolai M.; Oliver, Peter

doi:10.1038/ncomms15677

Cited by 36 publications

(35 citation statements)

References 56 publications

(86 reference statements)

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“…Other mechanisms, such as the ubiquitin ligase CBLB (Heiss-meyer et al, 2004; Jeon et al, 2004) or diacylglycerol kinase alpha (Olenchock et al, 2006), must also contribute to TCR desensitization, because signaling in NDFIPI-deficient CD8 + T cells remained lower than in non-tolerized control T cells. NDFIP1 may directly target mTOR signaling pathway components, and increased mTOR signaling was proposed to augment Ndfipl −/− regulatory T cell (Treg) proliferation and differentiation (Layman et al, 2017a); however, our data suggest that elevated mTOR signaling alone cannot explain the mutant CD8 + T cell phenotype. Our data also do not rule out a role for pathways beyond partially rescued TCR signaling in the Ndfip1 mutant cell phenotype, and further work is required to pinpoint the mechanism.…”

Section: Discussionmentioning

confidence: 70%

“…Ndfip1 -deficient CD4 + T cells resist both in vitro anti- CD3 induced anergy and in vivo tolerance to low or high antigen levels because of excessive interleukin (IL)-2 production, a failure to exit the cell cycle, and aberrant differentiation into T helper (Th) 2 or Th17 cells (Altin et al, 2014; Layman et al, 2017b; Oliver et al, 2006; Ramos-Hernández et al, 2013). Mice lacking NDFIP1 develop a fatal T cell-mediated inflammatory disease associated with T cell activation, regulatory T cell dysfunction, and Th2-mediated organ pathology (Altin et al, 2014; Beal et al, 2011; Layman et al, 2017a; Oliver et al, 2006). NDFIP1 likely plays similar roles in humans, because NDFIP1 polymorphisms and ITCH deficiency are associated with inflammatory and autoimmune diseases (Ferreira et al, 2011; Franke et al, 2010; Hu et al, 2011; International Multiple Sclerosis Genetics et al, 2011; Lohr et al, 2010; Ramon et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

et al. 2018

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SUMMARY Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

et al. 2018

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“…10,[23][24][25] Tregs can be highly glycolytic, but the primary Treg transcription factor, FoxP3, has also been shown to repress glycolysis and high rates of glucose metabolism can impair Treg suppressive capacity. 24,26,27 Individual effector T cell populations also differ, as glutamine metabolism is essential for CD4 Th17 cells, but effector differentiation of CD4 Th1 and CD8 cytotoxic T cells as well as that of classically activated M1-like macrophages is restrained by this pathway. [28][29][30] These differences likely reflect varied modes of regulation, roles, and requirements of specific tissue sites, and offer distinct opportunities to selectively modulate immunity ( Figure 2).…”

Section: Ba S Ic Mechanis Ms That Reg Ul Ate Immune Me Tabolis Mmentioning

confidence: 99%

Immunometabolism: From basic mechanisms to translation

Makowski

Chaib

Rathmell

2020

Immunological Reviews

246

190

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Immunometabolism has emerged as a major mechanism central to adaptive and innate immune regulation. From early observations that inflammatory cytokines were induced in obese adipose tissue and that these cytokines contributed to metabolic disease, it was clear that metabolism and the immunological state are inextricably linked. With a second research wave arising from studies in cancer metabolism to also study the intrinsic metabolic pathways of immune cells themselves and how those pathways influence cell fate and function, immunometabolism is a rapidly maturing area of research. Several key themes and goals drive the field. There is abundant evidence that metabolic pathways are closely tied to cell signaling and differentiation which leads different subsets of immune cells to adopt unique metabolic programs specific to their state and environment. In this way, metabolic signaling drives cell fate. It is also apparent that microenvironment greatly influences cell metabolism.Immune cells adopt programs specific for the tissues where they infiltrate and reside.Ultimately, a central goal of the field is to apply immunometabolism findings to the discovery of novel therapeutic strategies in a wide range of diseases, including cancer, autoimmunity, and metabolic syndrome. This review summarizes these facets of immunometabolism and highlights opportunities for clinical translation. K E Y W O R D S autoimmunity, immune-mediated diseases, infectious diseases, metThis article introduces a series of reviews covering Immunometabolism: From Basic Mechanisms to Translation appearing in Volume 295 of Immunological Reviews.

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“…WT and apoC-III Tg Tregs have comparable expression levels of mouse APOC3 (Supplementary Figure 1F). We stained Tregs with the cell cycle marker Ki-67 to identify which cells were actively proliferating [33]. Ki-67 staining was similar between WT and apoC-III Tg Tregs under both TCR-stimulated and unstimulated conditions ( Figure 4B).…”

Section: Apoc-iii Tg Tregs Are Phenotypically Comparable To Wt Tregsmentioning

confidence: 92%

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

Rodia

Tambini

et al. 2019

Preprint

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Objective: Cellular metabolism is a key regulator of CD4 + Foxp3 + regulatory T cell (Treg) homeostasis, but the foundational studies in this area use free fatty acid treatment as a proxy for plasma triglycerides. In vivo, plasma triglyceride is the main source of fatty acids for cells, not free fatty acids. Design/Results: Using apolipoprotein C-III transgenic and LDLr -/mice, we report that the loss of lipoprotein triglycerides transport in these models results in protection from DSS-colitis and accumulation of intestinal Tregs and plasma IL-10. Total loss of apoC-III increases colitis severity. Tregs exposed to apoC-III increase lipolysis and fatty acid oxidation and apoC-III inhibits Bodipytriglyceride uptake. Therapeutic treatment of WT mice with apoC-III-containing lipoproteins protects mice from colitis. Conclusion: Our data suggest that therapies that reduce apoC-III could have negative effects in patients who are at risk of IBD, and conversely, that apoC-III could be a new therapeutic target to stimulate intestinal Tregs and IL-10 for the management of IBD. These data identify apoC-III and lipoprotein metabolism as a novel regulator of tolerance in the intestine. Summary Box * What is already known about this subject:§ The relative capacity to use either glucose or FFA to generate acetyl CoA for mitochondrial fatty acid oxidation is a critical driver of Treg and T cell activity and proliferation. § ApoC-III is a known regulator of triglyceride and fatty acid metabolism in cells via LPL and LDLr endocytosis pathways § ApoC-III is reduced in Crohn's and Colitis patients. * What are the new findings:§ We show that Tregs express triglyceride transporters, and that LDLr expression is enriched in Tregs from the mesenteric lymph nodes. § We show that T cells are capable of endocytosing triglyceride from lipoproteins, and this process is inhibited by apoC-III. § Tregs from apoC-III Tg are metabolically unique from WT Tregs and they upregulate the genes of lipolysis, and have an increase in basal respiration. § The inhibition of TAG endocytosis, using 2 different models (LDLr KO and apoC-IIItransgenic mice), protects mice from colitis and stimulates the accumulation of Tregs and IL-10 in the gut. § Intraperitoneal delivery of apoC-III on chylomicrons protects WT mice from DSS colitis. * How might it impact on clinical practice in the foreseeable future?§ Due to the protective role apoC-III plays in these mouse models of colitis, IBD risk should be carefully considered before prescribing patient anti-apoC-III lipid-lowering therapies.the TAG for fuel through two processes: the hydrolysis of TAG to free fatty acids (FFA) via membrane-bound lipoprotein lipase (LPL) and the subsequent transport of those FFAs into the cell, or alternatively, endocytosis of lipoprotein TAG via the low-density lipoprotein receptor (LDLr), and the subsequent intracellular hydrolysis, oxidation, or storage of those FFAs. The way that a cell encounters a lipid fuel (either as a FFA bound to albumin or as a holoparticle lipoprotein) as sign...

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Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Cited by 36 publications

References 56 publications

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

Immunometabolism: From basic mechanisms to translation

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

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