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Background: Metabolic diseases represent a wide category of alterations affecting metabolism. These pathologies are notably marked by inflammation that implicates the immune system. Mucosal Associated Invariant (MAI)T cells are immune cells expressing a semi-invariant TCR able to recognize bacterial and fungal vitamin B metabolites. MAIT cells can promote inflammation and are present in many organs central to metabolism, suggesting a role in the etiopathology of these diseases. Scope of the review: Here, we will review what is known of the involvement of MAIT cells in metabolic pathologies in humans and mice. Major conclusions: MAIT cells are severely affected, overactivated with a frequency reduction and a phenotype shift from protective to deleterious. Therefore, they might be a novel target to treat, in particular, pancreas and liver metabolic diseases. Keywords: Mucosal associated invariant T cells, Metabolic disease, Liver, Pancreas, Diabetes, Microbiota

MAIT cells are innate-like T cells that are enriched in mucosal sites and tissues including adipose tissue and liver. They play an important role in immunity against microbial pathogens. Recently, it has been reported that MAIT cells could also be important in metabolic diseases and can be involved in setting up and maintaining chronic inflammation. In this review, we give an overview of recent advances in understanding MAIT cells role in the ethology of this diseases.

International audience; ObjectiveA common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the mechanistic bases underlying these features upon the diabesity cascade remain partly understood.MethodsHere, we show in mice that, independently of obesity, the induction of acute and global insulin resistance and associated hyperglycemia, upon treatment with an insulin receptor (IR) antagonist (S961), elicits gut hyperpermeability without triggering systemic inflammatory response.ResultsOf note, S961-treated diabetic mice display major defects of gut barrier epithelial functions, such as increased epithelial paracellular permeability and impaired cell-cell junction integrity. We also observed in these mice the early onset of a severe gut dysbiosis, as characterized by the bloom of pro-inflammatory Proteobacteria, and the later collapse of Paneth cells antimicrobial defense. Interestingly, S961 treatment discontinuation is sufficient to promptly restore both the gut microbial balance and the intestinal barrier integrity. Moreover, fecal transplant approaches further confirm that S961-mediated dybiosis contributes at least partly to the disruption of the gut selective epithelial permeability upon diabetic states.ConclusionsTogether, our results highlight that insulin signaling is an indispensable gatekeeper of intestinal barrier integrity, acting as a safeguard against microbial imbalance and acute infections by enteropathogens.

Natural killer T (NKT) cells are non-conventional T lymphocytes expressing a TCRαβ and several NK cell markers. Once activated, they can rapidly secrete large amounts of cytokines such as IFN-γ and IL-4. As a result they can favor both Th1 and Th2 immune responses and play a critical role in anti-pathogenic immune responses as well as in regulation of autoimmune diseases. It has now been clearly established that iNKT cells can be subdivided into three subpopulations: iNKT1, iNKT2 and iNKT17 cells. Each of these populations is characterized by the expression of a particular transcription factor, surface markers and cytokines making them functionally distinct. Interestingly, NOD mice developing autoimmune diabetes exhibit a high frequency of iNKT17 cells, which can participate in the disease.

Mast cell release of chymase is important in tissue remodeling and may participate in inflammation leading to fibrosis and organ failure. Here we analyzed the function of chymase in unilateral ureteral obstruction, an established accelerated model of renal tubulointerstitial fibrosis. Mice deficient in mouse mast cell protease 4 (mMCP4), the functional counterpart of human chymase, had increased obstruction-induced fibrosis when compared to wild-type mice indicating a protective effect of mMCP4. Engraftment of mast cell-deficient Kit(Wsh/Wsh) mice with wild type, but not mMCP4-deficient mast cells, restored protection confirming the role of mMCP4. Kidneys of mMCP4-deficient mice had higher levels of renal tubular damage, interstitial fibrosis, collagen deposition, increased α-smooth muscle actin, and decreased E-cadherin expression compared to the kidneys of wild-type mice. Further analysis showed an elevated inflammatory response in mMCP4-deficient mice with increased levels of kidney-infiltrating macrophages and T cells and local profibrotic TGF-β1 and CCL2. Granulated and degranulated mast cells and mMCP4 were mainly found in the kidney capsule, respectively, before and after ureteral obstruction. Analysis of mMCP4 substrates showed that it mediates its anti-fibrotic actions by degrading interstitial deposits of fibronectin, a known promoter of inflammatory cell infiltration and adhesion. Thus, mast cell released mMCP4 has anti-fibrotic potential in acutely induced obstructive nephropathy.

iNKT cells, CD1d dependent natural killer T cells are a unique population of T cells. The capacity of iNKT cells to produce regulatory cytokines first provided an indication of their regulatory potential. Later on, in experimental models as well as in patients afflicted with an auto-immune disease, such as Type 1 diabetes mellitus, multiple sclerosis, and systemic lupus erythematosus along with others, a deficit in iNKT cell number was observed, suggesting the role these cells may possibly have in the prevention of auto-immune diseases. More importantly, experimental strategies which focused on increasing the volume or stimulation of iNKT cells in laboratory animals, demonstrated an improved level of protection against the development of auto-immune diseases. This article reviews the mechanism of protection against autoimmunity by iNKT cells, discusses the obstacles against and indications for the potential use of iNKT cell manipulation in the treatment of human auto-immune diseases.

Invariant natural killer T (iNKT) cells play an important role in the immune response against various infectious agents. In this study we investigated their role in human defense against the varicella zoster virus. We observed decreased numbers of iNKT cells in patients who failed to control latent varicella zoster virus infection, e.g. underwent several reactivations of the virus. The residual population of iNKT cells expressed significantly higher levels of inhibitory receptor CD158a that was further up-regulated in the course of acute viral infection. Both of these abnormalities might contribute to impaired control of varicella zoster virus in human.

Invariant NKT (iNKT) cells are a unique T cell subset that upon activation promptly produce copious amounts of pro- and anti-inflammatory cytokines, thereby contributing to both innate and acquired immunity. Animal models of autoimmune diseases suggest that iNKT cells favor immune regulation because their absence enhances autoimmunity in some models, whereas their enrichment alleviates autoimmune manifestations. Moreover, convergent experiments indicate that therapeutic targeting of iNKT cells can potentiate their immunoregulatory properties. Therefore, iNKT cells are considered an attractive target for the treatment of human autoimmune disorders. However, in our opinion several concerns must be addressed before iNKT cell manipulation can be safely used for treating patients with autoimmune diseases. Here, we discuss the therapeutic potential of this approach, and its possible pitfalls.

To determine the precise regulatory effect of NKT cells on CD4(+) T cells involved in autoimmune diabetes, we developed an in vivo model in which transferred naive transgenic T cells are stimulated by their antigen in the presence or absence of NKT cells or in the presence of another conventional transgenic alphabeta T cell. The presence of NKT cells did not block the initial activation and expansion of the CD4(+) T cells but did inhibit their IL-2 and IFN-gamma production and later proliferation, resulting in an anergic phenotype. These CD4(+) T cells did not induce significant insulitis and were unable to destroy the beta cells. Thus, NKT cells prevent alphabeta CD4 T cell differentiation into effector cells.

IgA is the most abundant immunoglobulin in mucosal areas but is only the second most common antibody isotype in serum because it is catabolized faster than IgG. IgA exists in monomeric and polymeric forms that function through receptors expressed on effector cells. Here, we show that IgA Fc receptor(s) (FcalphaR) are expressed with or without the gamma chain on monocytes and neutrophils. gamma-less FcalphaR represent a significant fraction of surface FcalphaR molecules even on cells overexpressing the gamma chain. The FcalphaR-gamma2 association is up-regulated by phorbol esters and interferon-gamma. To characterize gamma-less FcalphaR functionally, we generated mast cell transfectants expressing wild-type human FcalphaR or a receptor with a point mutation (Arg --Leu at position 209) which was unable to associate with the gamma chain. Mutant gamma-less FcalphaR bound monomeric and polymeric human IgA1 or IgA2 but failed to induce exocytosis after receptor clustering. The two types of transfectant showed similar kinetics of FcalphaR-mediated endocytosis; however, the endocytosis pathways of the two types of receptor differed. Whereas mutant FcalphaR were localized mainly in early endosomes, those containing FcalphaR-gamma2 were found in endo-lysosomal compartments. Mutant gamma-less FcalphaR recycled the internalized IgA toward the cell surface and protected against IgA degradation. Cells expressing the two forms of FcalphaR, associated or unassociated with gamma chains, may thus have differential functions either by degrading IgA antibody complexes or by recycling serum IgA.

Introduction Le facteur de transcription Interferon Regulatory Factor-5 (irf5) est connu pour exercer un role crucial dans la polarisation des macrophages ainsi que dans l'activation de la reponse immunitaire adaptative. Recemment, nous avons revele l'importance d'IRF5 dans la progression du diabete de type-2 (DT2) en favorisant le developpement de l'obesite viscerale et la resistance a l'insuline (Dalmas, Toubal, Alzaid et al 2015 ; Nat Med). Le DT2 est souvent lie au developpement d'une steatohepatite non-alcoolique (NASH), caracterisee par le developpement d'une fibrose suite a l'activation du systeme immunitaire. Dans cette etude, nous nous sommes interesses au role d'irf5 dans l'inflammation et la fibrogenese hepatique. Materiels et Methodes Des souris invalidees pour irf5 dans les cellules myeloides (IRF5MacKO) et des souris sauvages ont ete sujettes a 1) un regime gras (HFD) et un regime deficient en methionine et choline (MCD) pour induire une steatose hepatique et 2) des injections tetrachlorure de carbone (CCl4) pour induire une fibrose hepatique. Une caracterisation phenotypique de ces souris a ete realisee sur le plan histologique, immunitaire et moleculaire. De plus, l'activation d'irf5 dans le foie de patients atteint de NASH a ete quantifiee. Resultats L'analyse phenotypique des macrophages hepatiques (cellules de Kupffer) suite aux traitements de souris sauvages demontre une augmentation de l'expression d'irf5. De plus, les marqueurs de la NASH correlent positivement avec l'augmentation d'IRF5 (e.g. accumulation des macrophages, augmentation des transaminases plasmatiques et de la fibrose). De maniere interessante, les souris IRF5MacKO soumises au regime MCD ou au traitement CCl4 ne developpent pas de fibrose en comparaison des souris sauvages. Ce phenotype protecteur est notamment orchestre par le changement de la polarisation des macrophages et la modification de la reponse immunitaire inhibant les processus de fibrogenese. L'activation d'irf5 a ete egalement verifiee dans l'analyse de foies de patients humains presentant differents stades de NASH. Conclusions Notre etude met en evidence l'effet deletere de l'activation d'irf5 dans les cellules myeloides au cours de la progression de la NASH. Le controle de la reponse immunitaire apparait une strategie therapeutique prometteuse afin de limiter la NASH.

Introduction Le diabete de type 1 est une maladie auto-immune caracterisee par la destruction des cellules β pancreatiques, productrices d’insuline. De nombreux travaux ont mis en evidence le role des lymphocytes T autoreactifs dans la mort des cellules β pancreatiques. Toutefois les mecanismes impliques dans l’activation initiale du systeme immunitaire, qui declenche la cascade d’evenements conduisant a la mort des cellules, sont encore mal definis. Materiels et methodes Nous avons analyse les etapes initiales du developpement du diabete de type 1 chez la souris NOD, qui developpe une maladie similaire a celle de l’homme. Resultats Chez les souris NOD de 2–3 semaines, la mort physiologique des cellules beta pancreatiques induit le recrutement et l’activation de cellules du systeme immunitaire innee, les neutrophiles et les cellules dendritiques plasmacytoides. Les lymphocytes B1 sont egalement recrutes dans les ilots et produisent des anticorps IgG anti-ADN. Les IgG anti-ADN complexees a l’ADN induit l’activation des neutrophiles, et leur production du peptide antimicrobien CRAMP. Le complexe multimoleculaire, compose d’IgG anti-ADN, self- DNA et CRAMP, active les cellules dendritiques plasmacytoides par le TLR9 et induit leur production d’IFN de type 1. L’IFN de type 1 a son tour va induire l’activation du systeme immunitaire adaptatif et la generation d’une forte reponse auto-reactive des lymphocytes T anti-ilots. Conclusion Dans la periode perinatale chez la souris NOD, une cascade d’activation des cellules immunitaires innees dans les ilots de Langerhans induit l’activation des lymphocytes T autoreactifs conduisant au developpement du diabete de type 1.