In humans, MAIT cells represent the most abundant T‐cell subset reacting against bacteria. MAIT cells belong to the evolutionarily conserved family of “preset” T cells that includes also NKT cells. ...Both subsets are selected by double positive thymocytes leading to common features such as PLZF expression. Preset T cells correspond to subsets prepositioned in specific tissue locations with preprogrammed versatile effector functions such as antimicrobial functions and possibly also metabolic control and tissue repair activity. Herein, we recall how several groups studying human samples discovered MAIT cells as T cells expressing either a restricted T‐cell receptors (TCR) repertoire or homogeneous and singular phenotypic and functional characteristics. We then highlight the main evolutionary features of this subset and its restricting element, MR1 (MHC‐related protein (1) with a striking coevolution of TRAV1 and MR1. We introduce another evolutionarily conserved invariant TCRalpha chain coevolving with another MHC class Ib molecule, called MHX, sharing phylogenetic features with MR1. We finally discuss the relationship between MAIT cells and other subsets reacting to microbial antigens or to compounds presented by MR1 in light of confounding experimental issues.
After a short history of MAIT discovery, we discuss the phylogenetic features of MAIT and related subsets. We provide a definition of MAIT cells and discuss some experimental issues with regard to the analysis of microbial reactivity.
Highlights ► MAIT cells recognize riboflavin derivatives originating from bacteria. ► Selection by hematopoietic thymic cells induce MAIT cell-specific features. ► MAIT cells are effector tissue ...targeted T cells resistant to xenobiotics. ► MAITs secrete IFN-γ and IL-17 and display context-dependent effector activities. ► Human MAITs encompass most, if not all, IL-17 producing CD8 T cells.
Mucosal-associated invariant T (MAIT) cells are abundant T cells with unique specificity for microbial metabolites. MAIT conservation along evolution indicates important functions, but their low ...frequency in mice has hampered their detailed characterization. Here, we performed the first transcriptomic analysis of murine MAIT cells. MAIT1 (RORγt
) and MAIT17 (RORγt
) subsets were markedly distinct from mainstream T cells, but quasi-identical to NKT1 and NKT17 subsets. The expression of similar programs was further supported by strong correlations of MAIT and NKT frequencies in various organs. In both mice and humans, MAIT subsets expressed gene signatures associated with tissue residency. Accordingly, parabiosis experiments demonstrated that MAIT and NKT cells are resident in the spleen, liver, and lungs, with LFA1/ICAM1 interactions controlling MAIT1 and NKT1 retention in spleen and liver. The transcriptional program associated with tissue residency was already expressed in thymus, as confirmed by adoptive transfer experiments. Altogether, shared thymic differentiation processes generate "preset" NKT and MAIT subsets with defined effector functions, associated with specific positioning into tissues.
Mucosal-associated invariant T (MAIT) cells are innate T cells expressing an invariant Vα7.2-Jα33 T-cell antigen receptor α chain and are enriched in mucosal-associated lymphoid tissues. Although the ...regulatory role of MAIT cells in experimental autoimmune encephalomyelitis has been determined, their role in multiple sclerosis (MS) has not been elucidated. In the present study, the character of MAIT cells in the peripheral blood of MS patients was analyzed. Compared with healthy controls, the frequency of MAIT cells in peripheral blood was significantly reduced in MS patients in remission and even more profoundly reduced in those with relapse. The frequency of MAIT cells reflected the disease activity, as they were reduced significantly in patients with active disease compared with stable patients, and when blood samples from patients undergoing attack were analyzed 2-3 months later, the frequency significantly increased in parallel with clinical recovery. The frequency of MAIT cells positively correlated with the frequency of CD4(+) invariant NKT cells and of CD56(bright) NK cells in healthy controls but not in MS patients. This suggests the existence of an immune-regulatory link between MAIT cells and these other cell populations with disruption of this cross talk in MS. Moreover, MAIT cells showed a suppressive activity against IFN-γ production by T cells in vitro. This suppression required cell contact but was independent of IL-10, inducible co-stimulator or the presence of B cells. Taken together, these results suggest an immune-regulatory role of MAIT cells in MS through suppression of pathogenic T(h)1 cells.
Obesity is associated with low-grade chronic inflammation promoting insulin-resistance and diabetes. Gut microbiota dysbiosis is a consequence as well as a driver of obesity and diabetes. ...Mucosal-associated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting bacterial ligands. Here we show that during obesity MAIT cells promote inflammation in both adipose tissue and ileum, leading to insulin resistance and impaired glucose and lipid metabolism. MAIT cells act in adipose tissue by inducing M1 macrophage polarization in an MR1-dependent manner and in the gut by inducing microbiota dysbiosis and loss of gut integrity. Both MAIT cell-induced tissue alterations contribute to metabolic dysfunction. Treatment with MAIT cell inhibitory ligand demonstrates its potential as a strategy against inflammation, dysbiosis and metabolic disorders.
MAIT cells express an invariant TCR that recognizes non-peptidic microbial antigens presented by the non-polymorphic MHCI-like molecule, MR1. We briefly describe how the antigens recognized by MAIT ...cells are generated from an unstable precursor of the riboflavin (Vitamin B2) biosynthesis pathway, as well as the main features of MAIT cells in comparison with other related T cell subsets. In silico analysis of bacterial genomes shows that the riboflavin biosynthesis pathway is highly prevalent in all groups of Prokaryotes with, however, notable exceptions. We discuss the putative functions and the evolution of the MAIT/MR1 couple: it appeared in the ancestors of mammals and is highly conserved across this group, but was independently lost in three orders. We describe the four instances of known invariant TCR and MHC-I-like molecules encountered in Vertebrates. Both T cells bearing semi-invariant TCR and the associated, evolutionarily conserved MHC-I related molecules have been found in mammals or in amphibians, which suggests that other MHC1-like/invariant TCR couples might be present in other classes of Vertebrates to detect generic microbial compounds. This allows us to discuss how the recognition of riboflavin precursor derivatives by the MAIT TCR may be a way to detect invasive microbes in specific organs, and may epitomize other invariant T cell systems across vertebrates.
In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and ...detect minimal residual disease after surgery.
Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 (
) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS).
Forty-six patients with nonmetastatic TNBC were enrolled.
mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS (
= 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index (
= 0.003), tumor grade (
= 0.003), and stage (
= 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free (
< 0.001) and overall (
= 0.006) survival.
Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival.
Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by ...regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy.
Mucosal associated invariant T cells (MAIT) are innate T lymphocytes that detect a large variety of bacteria and yeasts. This recognition depends on the detection of microbial compounds presented by ...the evolutionarily conserved major-histocompatibility-complex (MHC) class I molecule, MR1. Here we show that MAIT cells display cytotoxic activity towards MR1 overexpressing non-hematopoietic cells cocultured with bacteria. The NK receptor, CD161, highly expressed by MAIT cells, modulated the cytokine but not the cytotoxic response triggered by bacteria infected cells. MAIT cells are also activated by and kill epithelial cells expressing endogenous levels of MRI after infection with the invasive bacteria Shigella flexneri. In contrast, MAIT cells were not activated by epithelial cells infected by Salmonella enterica Typhimurium. Finally, MAIT cells are activated in human volunteers receiving an attenuated strain of Shigella dysenteriae-1 tested as a potential vaccine. Thus, in humans, MAIT cells are the most abundant T cell subset able to detect and kill bacteria infected cells.
Exosomes are nanovesicles originating from late endosomal compartments and secreted by most living cells in ex vivo cell culture conditions. The interest in exosomes was rekindled when B-cell and ...dendritic cell-derived exosomes were shown to mediate MHC-dependent immune responses. Despite limited understanding of exosome biogenesis and physiological relevance, accumulating evidence points to their bioactivity culminating in clinical applications in cancer. This review focuses on the preclinical studies exploiting the immunogenicity of dendritic cell-derived exosomes (Dex) and will elaborate on the past and future vaccination trials conducted using Dex strategy in melanoma and non-small cell lung cancer patients.
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