MAIT cells: Conserved watchers on the wall.

MAIT cells are innate-like T cells residing in barrier tissues such as the lung, skin, and intestine. Both the semi-invariant T cell receptor of MAIT cells and the restricting element MR1 are deeply conserved across mammals, indicating non-redundant functions linked to antigenic specificity. MAIT cells across species concomitantly express cytotoxicity and tissue-repair genes, suggesting versatile functions.

Innate-like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation.

How T-cell receptor (TCR) characteristics determine subset commitment during T-cell development is still unclear. Here, we addressed this question for innate-like T cells, mucosal-associated invariant T (MAIT) cells, and invariant natural killer T (iNKT) cells. MAIT and iNKT cells have similar developmental paths, leading in mice to two effector subsets, cytotoxic (MAIT1/iNKT1) and IL17-secreting (MAIT17/iNKT17).

A conserved transcriptional program for MAIT cells across mammalian evolution.

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.

Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing.

Tissue repair processes maintain proper organ function following mechanical or infection-related damage. In addition to antibacterial properties, mucosal associated invariant T (MAIT) cells express a tissue repair transcriptomic program and promote skin wound healing when expanded. Herein, we use a human-like mouse model of full-thickness skin excision to assess the underlying mechanisms of MAIT cell tissue repair function.

CD1 and MR1: An update after a long-awaited reunion.

CD1 molecules and the MHC-related protein 1 (MR1) present lipid and small molecule antigens, respectively, for T cell surveillance. The biology of these molecules, the antigens they present, and the T cells that respond to them were recently discussed during the 12 International CD1-MR1 Meeting held in Gothenburg, Sweden.

Correction: The intracellular pathogen escapes from adaptive immunity by metabolic adaptation.

This study shows that this metabolic adaptation allows the intracellular bacterial pathogen to escape recognition by the host adaptive immunity.

γδ T, NKT, and MAIT Cells During Evolution: Redundancy or Specialized Functions?

Innate-like T cells display characteristics of both innate lymphoid cells (ILCs) and mainstream αβ T cells, leading to overlapping functions of innate-like T cells with both subsets. In this review, we show that although innate-like T cells are probably present in all vertebrates, their main characteristics are much better known in amphibians and mammals. Innate-like T cells encompass both γδ and αβ T cells.

The intracellular pathogen escapes from adaptive immunity by metabolic adaptation.

Intracellular pathogens lose many metabolic genes during their evolution from free-living bacteria, but the pathogenic consequences of their altered metabolic programs on host immunity are poorly understood. Here, we show that a pathogenic strain of (FT) has five amino acid substitutions in RibD, a converting enzyme of the riboflavin synthetic pathway responsible for generating metabolites recognized by mucosal-associated invariant T (MAIT) cells. Metabolites from a free-living strain, (FN), activated MAIT cells in a T-cell receptor (TCR)-dependent manner, whereas introduction of FT-type to the free-living strain was sufficient to attenuate this activation in both human and mouse MAIT cells.

MAIT cell development in mice and humans.

MAIT cells arise in the thymus following rearrangement of a T cell receptor (TCR) reactive against microbial vitamin B2-derived metabolites presented by the MHC-Ib molecule, MR1. Mechanisms that are conserved in mammals ensure the frequent production of MR1-restricted TCRs and the intra-thymic differentiation of MR1-restricted thymocytes into effector cells. Upon thymic egress and migration into non-lymphoid tissues, additional signals modulate MAIT cell functions according to each local tissue environment.

MAIT Cell Development and Functions: the Microbial Connection.

Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved T cell subset, which reacts to most bacteria through T cell receptor (TCR)-mediated recognition of metabolites derived from the vitamin B2 biosynthetic pathway. Microbiota-derived signals affect all stages of MAIT cell biology including intra-thymic development, peripheral expansion, and functions in specific organs. In tissues, MAIT cells can integrate multiple signals and display effector functions involved in the defense against infectious pathogens.

Opposing peripheral fates of tissue-restricted self antigen-specific conventional and regulatory CD4 T cells.

The development of self antigen-specific T cells is influenced by how the self antigen is expressed. Here, we created a mouse in which a model self antigen is conditionally expressed in different tissue environments. Using peptide:MHCII tetramer-based cell enrichment methods, we examined the development of corresponding endogenous self antigen-specific CD4 T cell populations.

Microbial metabolites control the thymic development of mucosal-associated invariant T cells.

How the microbiota modulate immune functions remains poorly understood. Mucosal-associated invariant T (MAIT) cells are implicated in mucosal homeostasis and absent in germ-free mice. Here, we show that commensal bacteria govern murine MAIT intrathymic development, as MAIT cells did not recirculate to the thymus.

Molecular mechanisms of lineage decisions in metabolite-specific T cells.

Mucosal-associated invariant T cells (MAIT cells) recognize the microbial metabolite 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) presented by the MHC class Ib molecule, MR1. MAIT cells acquire effector functions during thymic development, but the mechanisms involved are unclear. Here we used single-cell RNA-sequencing to characterize the developmental path of 5-OP-RU-specific thymocytes.

MAIT cells: programmed in the thymus to mediate immunity within tissues.

MAIT cells are an evolutionarily conserved T cell subset recognizing ubiquitous microbial metabolites. Herein, we review recent literature showing that MAIT cells can be divided into type 1 and type 17 subsets, which acquire a tissue resident differentiation program in the thymus and localize in specific tissues. We also discuss the nature and in vivo availability of the different agonist and antagonist MAIT ligands with potential consequences for MAIT cell biology.

A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets.

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.

MAIT cells: an historical and evolutionary perspective.

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.

Unconventional or Preset αβ T Cells: Evolutionarily Conserved Tissue-Resident T Cells Recognizing Nonpeptidic Ligands.

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.

MHC class I-related molecule, MR1, and mucosal-associated invariant T cells.

The MHC-related 1, MR1, molecule presents a new class of microbial antigens (derivatives of the riboflavin [Vitamin B2] biosynthesis pathway) to mucosal-associated invariant T (MAIT) cells. This raises many questions regarding antigens loading and intracellular trafficking of the MR1/ligand complexes. The MR1/MAIT field is also important because MAIT cells are very abundant in humans and their frequency is modified in many infectious and non-infectious diseases.

Role of the MHC restriction during maturation of antigen-specific human T cells in the thymus.

In the thymus, a T-cell repertoire able to confer protection against infectious and noninfectious agents in a peptide-dependent, self-MHC-restricted manner is selected. Direct detection of Ag-specific thymocytes, and analysis of the impact of the expression of the MHC-restricting allele on their frequency or function has never been studied in humans because of the extremely low precursor frequency. Here, we used a tetramer-based enrichment protocol to analyze the ex vivo frequency and activation-phenotype of human thymocytes specific for self, viral and tumor-antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele.

CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion.

Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all.

Analysis of relationships between peptide/MHC structural features and naive T cell frequency in humans.

The structural rules governing peptide/MHC (pMHC) recognition by T cells remain unclear. To address this question, we performed a structural characterization of several HLA-A2/peptide complexes and assessed in parallel their antigenicity, by analyzing the frequency of the corresponding Ag-specific naive T cells in A2(+) and A2(-) individuals, as well as within CD4(+) and CD8(+) subsets. We were able to find a correlation between specific naive T cell frequency and peptide solvent accessibility and/or mobility for a subset of moderately prominent peptides.

Characterization of the human CD4(+) T-cell repertoire specific for major histocompatibility class I-restricted antigens.

While CD4(+) T lymphocytes usually recognize antigens in the context of major histocompatibility (MHC) class II alleles, occurrence of MHC class-I restricted CD4(+) T cells has been reported sporadically. Taking advantage of a highly sensitive MHC tetramer-based enrichment approach allowing detection and isolation of scarce Ag-specific T cells, we performed a systematic comparative analysis of HLA-A*0201-restricted CD4(+) and CD8(+) T-cell lines directed against several immunodominant viral or tumoral antigens. CD4(+) T cells directed against every peptide-MHC class I complexes tested were detected in all donors.