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Intestinal inflammation shifts microbiota composition and metabolism. How the host monitors and responds to such changes remains unclear. Here, we describe a protective mechanism by which mucosal-associated invariant T (MAIT) cells detect microbiota metabolites produced upon intestinal inflammation and promote tissue repair. At steady state, MAIT ligands derived from the riboflavin biosynthesis pathway were produced by aerotolerant bacteria residing in the colonic mucosa. Experimental colitis triggered luminal expansion of riboflavin-producing bacteria, leading to increased production of MAIT ligands. Modulation of intestinal oxygen levels suggested a role for oxygen in inducing MAIT ligand production. MAIT ligands produced in the colon rapidly crossed the intestinal barrier and activated MAIT cells, which expressed tissue-repair genes and produced barrier-promoting mediators during colitis. Mice lacking MAIT cells were more susceptible to colitis and colitis-driven colorectal cancer. Thus, MAIT cells are sensitive to a bacterial metabolic pathway indicative of intestinal inflammation. Editor's summary: Changes in the gut microbiota have been linked to intestinal inflammation, but how these shifts are sensed by the host is not completely understood. Using an experimental colitis model in mice, El Morr et al. defined a role for mucosal-associated invariant T (MAIT) cells in sensing increases in MAIT ligands associated with the expansion of riboflavin-producing aerotolerant bacteria in the gut lumen. MAIT cells are then activated upon sensing these ligands and produce anti-inflammatory molecules and mediators of tissue repair. In the absence of MAIT cells, mice are more susceptible to colitis pathology and progression to colorectal cancer. —Christiana Fogg [ABSTRACT FROM AUTHOR]

CD4+ T cell antitumor responses have mostly been studied in transplanted tumors expressing secreted model antigens (Ags), while most mutated proteins in human cancers are not secreted. The fate of Ag-specific CD4+ T cells recognizing a cytoplasmic Ag in mice bearing autochthonous tumors is still unclear. Here we show, using a genetically engineered lung adenocarcinoma mouse model, that naive tumor-specific CD4+ T cells are activated and proliferate in the tumor-draining lymph node (TdLN) but do not differentiate into effectors or accumulate in tumors. Instead, these CD4+ T cells are driven toward anergy or peripherally-induced Treg (pTreg) differentiation, from the early stage of tumor development. This bias toward immune suppression is restricted to the TdLN, and is maintained by Tregs enriched in the tumor Ag-specific cell population. Thus, tumors may enforce a dominant inhibition of the anti-tumor CD4 response in the TdLN by recapitulating peripheral self-tolerance mechanisms. [ABSTRACT FROM AUTHOR]

A majority of T cells bearing the αβ T cell receptor (TCR) are specific for peptides bound to polymorphic classical major histocompatibility complex (MHC) molecules. Smaller subsets of T cells are reactive toward various nonpeptidic ligands associated with nonpolymorphic MHC class-Ib (MHC-Ib) molecules. These cells have been termed unconventional for decades, even though only the composite antigen is different from the one seen by classical T cells. Herein, we discuss the identity of these particular T cells in light of the coevolution of their TCR and MHC-Ib restricting elements. We examine their original thymic development: selection on hematopoietic cells leading to the acquisition of an original differentiation program. Most of these cells acquire memory cell features during thymic maturation and exhibit unique patterns of migration into peripheral nonlymphoid tissues to become tissue resident. Thus, these cells are termed preset T cells, as they also display a variety of effector functions. They may act as microbial or danger sentinels, fight microbes, or regulate tissue homeostasis. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by focal demyelination patches associated with inflammatory infiltrates containing T lymphocytes. For decades, CD4+ T cells have been recognized as playing a major role in the disease, especially in animal models, which has led to the development of several therapies. However, interest has recently developed in the involvement of CD8+ T cells in MS following the analysis of infiltrating T cells in human brain lesions. A broad range of evidence now suggests that the pathological role of this T cell subset in MS may have been underestimated. In this review, we summarize the literature implicating CD8+ T cells in the pathophysiology of MS. We present data from studies in the fields of genetics, anatomopathology and immunology, mainly in humans but also in animal models of MS. Altogether, this strongly suggests that CD8+ T cells may be major effectors in the disease process, and that the development of treatments specifically targeting this subset would be germane. [ABSTRACT FROM AUTHOR]

Background: Astrocytes, the most abundant cell population in mammal central nervous system (CNS), contribute to a variety of functions including homeostasis, metabolism, synapse formation, and myelin maintenance. White matter (WM) reactive astrocytes are important players in amplifying autoimmune demyelination and may exhibit different changes in transcriptome profiles and cell function in a disease-context dependent manner. However, their transcriptomic profile has not yet been defined because they are difficult to purify, compared to gray matter astrocytes. Here, we isolated WM astrocytes by laser capture microdissection (LCM) in a murine model of multiple sclerosis to better define their molecular profile focusing on selected genes related to inflammation. Based on previous data indicating anti-inflammatory effects of estrogen only at high nanomolar doses, we also examined mRNA expression for enzymes involved in steroid inactivation. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL6 mice with MOG35-55 immunization. Fluorescence activated cell sorting (FACS) analysis of a portion of individual spinal cords at peak disease was used to assess the composition of immune cell infiltrates. Using custom Taqman low-density-array (TLDA), we analyzed mRNA expression of 40 selected genes from immuno-labeled laser-microdissected WM astrocytes from lumbar spinal cord sections of EAE and control mice. Immunohistochemistry and double immunofluorescence on control and EAE mouse spinal cord sections were used to confirm protein expression in astrocytes. Results: The spinal cords of EAE mice were infiltrated mostly by effector/memory T CD4+ cells and macrophages. TLDA-based profiling of LCM-astrocytes identified EAE-induced gene expression of cytokines and chemokines as well as inflammatory mediators recently described in gray matter reactive astrocytes in other murine CNS disease models. Strikingly, SULT1A1, but not other members of the sulfotransferase family, was expressed in WM spinal cord astrocytes. Moreover, its expression was further increased in EAE. Immunohistochemistry on spinal cord tissues confirmed preferential expression of this enzyme in WM astrocytic processes but not in gray matter astrocytes. Conclusions: We described here for the first time them RNA expression of several genes in WM astrocytes in a mouse model of multiple sclerosis. Besides expected pro-inflammatory chemokines and specific inflammatory mediators increased during EAE, we evidenced relative high astrocytic expression of the cytoplasmic enzyme SULT1A1. As the sulfonation activity of SULT1A1 inactivates estradiol among other phenolic substrates, its high astrocytic expression may account for the relative resistance of this cell population to the anti-neuroinflammatory effects of estradiol. Blocking the activity of this enzyme during neuroinflammation may thus help the injured CNS to maintain the anti-inflammatory activity of endogenous estrogens or limit the dose of estrogen co-regimens for therapeutical purposes. [ABSTRACT FROM AUTHOR]

Objective In multiple sclerosis ( MS), central nervous system ( CNS), cerebrospinal fluid ( CSF), and blood display TCR clonal expansions of CD8+ T cells. These clones have been assumed - but never demonstrated - to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8+ T cells in the disease. Methods For the first time, TCR V β repertoire from paired blood (purified CD8+ and CD4+ T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 ( CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8+ T cells were characterized by fluorescent staining. Results TCR V β repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8+ T cells. In parallel, we showed that blood oligoclonal CD8+ T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. Interpretation This study highlights the predominant implication of CD8+ T cells in MS pathophysiology and demonstrates that potentially aggressive CD8+ T cells can be easily identified and characterized from blood and CSF samples. [ABSTRACT FROM AUTHOR]

Although there is no evidence for a role of anti-MOG antibodies in adult MS, no information on B lymphocytes with MOG-committed BCR is available. We report here on the frequency of anti-MOG B cells forming rosettes with polystyrene beads (BBR) covalently bound to the extracellular domain of rhMOG in 38 relapsing-remitting patients (RRMS) and 50 healthy individuals (HI). We show a substantial proportion of circulating anti-MOG-BBR in both RRMS and HI. Strikingly, MOG-specific B cells frequencies were lower in MS than in HI. Anti-MOG antibodies measured by a cell-based assay were not different between MS patients and controls, suggesting a specific alteration of anti-MOG B cells in MS. Although anti-MOG-BBR were higher in CNS fluid than in blood, no difference was observed between MS and controls. Lower frequency of MOG-BBR in MS was not explained by an increased apoptosis, but a trend for lower proliferative capacity was noted. Despite an efficient B cell transmigration across brain derived endothelial cells, total and anti-MOG B cells transmigration was similar between MS and HI. The striking alteration in MOG-specific B cells, independent of anti-MOG antibody titers, challenges our view on the role of MOG-specific B cells in MS. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Loss of IL-10 secretion by regulatory B lymphocytes in multiple sclerosis patients," by several researchers including, Laure Michel, Nicolas Degauque, and Alexandra Garcia is presented.

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved T cells that recognize microbial metabolites. They are abundant in humans and conserved during mammalian evolution, which suggests that they have important nonredundant functions. In this article, we discuss the evolutionary conservation of MAIT cells and describe their original developmental process. MAIT cells exert a wide variety of effector functions, from killing infected cells and promoting inflammation to repairing tissues. We provide insights into these functions and discuss how they result from the context of stimulation encountered by MAIT cells in different tissues and pathological settings. We describe how MAIT cell numbers and features are modified in disease states, focusing mainly on in vivo models. Lastly, we discuss emerging strategies to manipulate MAIT cells for therapeutic purposes.

Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage., (© 2024 Lucibello et al.)

Mucosal-associated invariant T (MAIT) cells harbor evolutionarily conserved TCRs, suggesting important functions. As human and mouse MAIT functional programs appear distinct, the evolutionarily conserved MAIT functional features remain unidentified. Using species-specific tetramers coupled to single-cell RNA sequencing, we characterized MAIT cell development in six species spanning 110 million years of evolution. Cross-species analyses revealed conserved transcriptional events underlying MAIT cell maturation, marked by ZBTB16 induction in all species. MAIT cells in human, sheep, cattle, and opossum acquired a shared type-1/17 transcriptional program, reflecting ancestral features. This program was also acquired by human iNKT cells, indicating common differentiation for innate-like T cells. Distinct type-1 and type-17 MAIT subsets developed in rodents, including pet mice and genetically diverse mouse strains. However, MAIT cells further matured in mouse intestines to acquire a remarkably conserved program characterized by concomitant expression of type-1, type-17, cytotoxicity, and tissue-repair genes. Altogether, the study provides a unifying view of the transcriptional features of innate-like T cells across evolution., (© 2023 Bugaut et al.)

Adoptive transfer of immunoregulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Mucosal-associated invariant T (MAIT) cells were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAIT cells in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic GVHD model. We found that MAIT cells, whether freshly purified or short-term expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAIT cells greatly delayed GVHD onset and decreased severity when transferred early after PBMC injection but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels and increased IL-10 levels. MAIT cells acted partly in a contact-dependent manner, which likely required direct interaction of their T cell receptor with MHC class I-related molecule (MR1) induced on host-reactive T cells. These results support the setup of clinical trials using MAIT cells as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders.

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 neg ) 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., (© 2018 Salou et al.)

CD4 + T cell antitumor responses have mostly been studied in transplanted tumors expressing secreted model antigens (Ags), while most mutated proteins in human cancers are not secreted. The fate of Ag-specific CD4 + T cells recognizing a cytoplasmic Ag in mice bearing autochthonous tumors is still unclear. Here we show, using a genetically engineered lung adenocarcinoma mouse model, that naive tumor-specific CD4 + T cells are activated and proliferate in the tumor-draining lymph node (TdLN) but do not differentiate into effectors or accumulate in tumors. Instead, these CD4 + T cells are driven toward anergy or peripherally-induced Treg (pTreg) differentiation, from the early stage of tumor development. This bias toward immune suppression is restricted to the TdLN, and is maintained by Tregs enriched in the tumor Ag-specific cell population. Thus, tumors may enforce a dominant inhibition of the anti-tumor CD4 response in the TdLN by recapitulating peripheral self-tolerance mechanisms.

Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2 + CD161 high CD4 - T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2 + CD161 high T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2 + and Vα7.2 - CD161 high T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood Vα7.2 + CD161 high T cells, the minority recognizing MR1:5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1:5-OP-RU reactive Vα7.2 + CD161 high T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other Vα7.2 + CD161 high and Vα7.2 - CD161 high populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCRαβ chains recognizing MR1-restricted microbial antigens., (© 2018 Ben Youssef et al.)

Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic β-cells by the immune system that involves innate and adaptive immune cells. Mucosal-associated invariant T cells (MAIT cells) are innate-like T-cells that recognize derivatives of precursors of bacterial riboflavin presented by the major histocompatibility complex (MHC) class I-related molecule MR1. Since T1D is associated with modification of the gut microbiota, we investigated MAIT cells in this pathology. In patients with T1D and mice of the non-obese diabetic (NOD) strain, we detected alterations in MAIT cells, including increased production of granzyme B, which occurred before the onset of diabetes. Analysis of NOD mice that were deficient in MR1, and therefore lacked MAIT cells, revealed a loss of gut integrity and increased anti-islet responses associated with exacerbated diabetes. Together our data highlight the role of MAIT cells in the maintenance of gut integrity and the control of anti-islet autoimmune responses. Monitoring of MAIT cells might represent a new biomarker of T1D, while manipulation of these cells might open new therapeutic strategies.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by focal demyelination patches associated with inflammatory infiltrates containing T lymphocytes. For decades, CD4(+) T cells have been recognized as playing a major role in the disease, especially in animal models, which has led to the development of several therapies. However, interest has recently developed in the involvement of CD8(+) T cells in MS following the analysis of infiltrating T cells in human brain lesions. A broad range of evidence now suggests that the pathological role of this T cell subset in MS may have been underestimated. In this review, we summarize the literature implicating CD8(+) T cells in the pathophysiology of MS. We present data from studies in the fields of genetics, anatomopathology and immunology, mainly in humans but also in animal models of MS. Altogether, this strongly suggests that CD8(+) T cells may be major effectors in the disease process, and that the development of treatments specifically targeting this subset would be germane.