Intestinal inflammation continues in a subset of patients with celiac disease despite a gluten-free diet. Here, by applying multi-omic single-cell analysis to duodenal biopsies, we found that low-grade malignancies with lymphoma driver mutations in patients with refractory celiac disease type 2 (RCD2) are comprised by surface CD3-negative (sCD3-) lymphocytes stalled at an innate lymphoid cell (ILC)-progenitor T cell stage undergoing extensive TRA, TRB, and TRD TCR recombination. In people with refractory celiac disease type 1 (RCD1), a disease currently lacking explanation, we identified sCD3+ T cells with lymphoma driver mutations in 6 of 10 individuals with RCD1 and in one of the patients with active, recently diagnosed celiac disease. Furthermore, the mutant T cells formed large TCRαβ clones and displayed inflammatory and cytotoxic molecular profiles. Thus, accumulation of lymphoma driver-mutated T cells and sCD3- progenitors may contribute to chronic, nonresponsive celiac disease.

The major histocompatibility complex class-I related protein, MR1, is an evolutionarily conserved antigen presenting molecule that binds and displays organic metabolites to T cells, including mucosal associated invariant T (MAIT) cells and diverse MR1-restricted T cells (MR1T). Structural studies have elucidated how MR1 can accommodate a range of chemical scaffolds that arise from foreign, synthetic, and self-metabolites, although the full spectrum of metabolites that MR1 presents remains unclear. Presently, MAIT and MR1T cell recognition of MR1-antigen complexes represents a new immune recognition paradigm and is emerging as a critical player in protective immunity, aberrant immunity, tumor immunity, and tissue repair. Moreover, the limited allelic variation of MR1 makes it an attractive therapeutic target. This review will address the unique features and capability of the MR1 molecule to display several classes of small molecules for T cell surveillance. We will also address the molecular basis underlying MAIT and MR1T TCR recognition of MR1-binding ligands.

Mucosal-associated invariant T-cells (MAIT) have been associated with lung cancer and pulmonary infections. The treatment of patients with cancer or infections includes host-directed therapies (HDTs). MAIT play a role in shaping the 'milieu interne' in cancer and infections and this review addresses the biology of MAIT in pulmonary pathophysiology.

MAIT represent an attractive target for therapy in pulmonary malignancies and infections. T-cells are often difficult to exploit therapeutically due to the diversity of both T-cell receptor (TCR) repertoire and its ligandome. MAIT-cells are restricted by the major histocompatibility complex class I-related gene protein (MR1) that presents nondefined tumor-associated targets, bacterial products, vitamin and drug derivates. Due to their plasticity in gene expression, MAIT are able to conversely switch from IFN-γ to IL-17 production. Both cytokines play a key role in protective immune responses in infections and malignancies. MAIT-derived production of interleukin (IL)-17/TGF-β shapes the tumor micro-environment (TME), including tissue re-modelling leading to pulmonary fibrosis and recruitment of neutrophils. MAIT contribute to the gut-lung axis associated with clinical improved responses of patients with cancer to checkpoint inhibition therapy. MAIT are at the crossroad of HDTs targeting malignant and infected cells. Clinical presentations of overt inflammation, protective immune responses and tissue re-modeling are reviewed along the balance between Th1, Th2, Th9, and Th17 responses associated with immune-suppression or protective immune responses in infections.

MAIT shape the TME in pulmonary malignancies and infections. Drugs targeting the TME and HDTs affect MAIT that can be explored to achieve improved clinical results while curbing overt tissue-damaging immune responses.

Mucosal-associated invariant T (MAIT) cells are unconventional innate-like T cells abundant in human mucosal tissues and are associated with protective responses to microbial infections. MAIT cells have the capacity for rapid effector functions, including the secretion of cytokines and cytotoxic molecules. In this study, we examined the longitudinal circulating MAIT cell response to the live attenuated oral vaccine Ty21a (Ty21a) against Salmonella enterica serovar Typhi (S. Typhi). We enrolled healthy adults who received a course of oral live-attenuated S. Typhi strain Ty21a vaccine and assessed peripheral blood MAIT cell longitudinal responses pre-vaccination, and at seven days and one-month post-vaccination, using flow cytometry, cell migration, and tetramer decay assays. We showed that following vaccination, circulating MAIT cells were lower in frequency, but were more activated, and had higher levels of gut-homing marker integrin α4β7 and chemokine receptors CCR9 and CCR6, suggesting the potential of MAIT cells to migrate to mucosal sites. We found no significant differences in MAIT cell functionality, cytotoxicity and T-cell receptor avidity, except in TNF expression, which was higher post-vaccination. We show that MAIT cell immune responses are modulated post-vaccination against S. Typhi. This study contributes to our understanding of MAIT cells' potential role in oral vaccination against bacterial mucosal pathogens.

Early immune dynamics during the initiation of fatal tularemia caused by Francisella tularensis infection remain unknown. Unto that end, we generated a transcriptomic map at single-cell resolution of the innate-like lymphocyte responses to F. tularensis live vaccine strain (LVS) infection of mice. We found that both interferon-γ (IFN-γ)-producing type 1 and interleukin-17 (IL-17)-producing type 3 innate-like lymphocytes expanded in the infected lungs. Natural killer (NK) and NKT cells drove the type 1 response, whereas mucosal-associated invariant T (MAIT) and γδ T cells drove the type 3 response. Furthermore, tularemia-like disease resistant NKT cell-deficient, Cd1d -/- mice accumulated more MAIT1 cells, MAIT17 cells, and cells with a hybrid phenotype between MAIT1 and MAIT17 cells than wild-type mice. Critically, adoptive transfer of LVS-activated MAIT cells from Cd1d -/- mice, which were enriched in MAIT17 cells, was sufficient to protect LVS-susceptible, immunodeficient RAG2 -/- mice from severe LVS infection-inflicted pathology. Collectively, our findings position MAIT cells as potential mediators of IL-17-dependent protection from pulmonary tularemia-like disease.

Hematogenous disseminated tuberculosis (DTB) has an unclear etiology that likely involves multiple factors. Understanding the underlying immunological characteristics of DTB is crucial for elucidating its pathogenesis.

We conducted single-cell RNA transcriptome and T cell receptor (TCR) sequencing on samples from seven DTB patients. Additionally, we integrated and analyzed data from two published profiles of latent TB infection, three active TB cases, and two healthy controls.

Our analysis revealed a significantly higher proportion of inflammatory immune cells (e.g., monocytes and macrophages) in DTB patients, along with a notably lower abundance of various lymphocytes (including T cells, B cells, and plasma cells), suggesting that lymphopenia is a prominent feature of the disease. T cell pseudotime analysis indicated a decrease in the expression of most hypervariable genes over time, pointing to T cell functional exhaustion. Furthermore, a marked absence of mucosal-associated invariant T (MAIT) cells was observed in the peripheral blood of DTB patients. In the TCR repertoire, specific polymorphisms (TRAV9-2, TRAV13-1, TRBV20-1, and TRBV5-1) and dominant clones (TRAJ49, TRBJ2-7, and TRBJ2-1) were identified. Analysis of the complementarity determining region 3 (CDR3) showed that the most frequent combination was TRAV1-2/TRAJ33, with the motif "CAAMD" being significantly reduced in DTB patients.

These findings suggest that lymphopenia and T cell exhaustion, along with unique TCR signatures, may play critical roles in DTB pathogenesis. The reduced "CAAMD" motif and altered TCR clonotypes provide novel insights into the complex cellular dynamics associated with the disease, potentially offering new avenues for targeted immunological interventions.

Tuberculosis (TB) remains a leading cause of death globally, with nearly half of TB patients experiencing iron deficiency. The role of iron supplementation as an adjunct therapy remains controversial. This study examines the impact of iron deficiency on TB progression and immune function. We conducted a case-control study involving 808 pulmonary TB patients recruited from Changzhou Third People's Hospital (2018-2022) to investigate the association between serum iron levels and TB severity. Additionally, we evaluated the relationship between baseline serum iron levels and pulmonary lesion characteristics during antituberculosis treatment using a cohort study of 89 patients. We observed that low serum iron was associated with more severe lung symptoms, decreased MAIT, Vδ2+, and Treg cell percentages, and increased interleukin-1β (IL-1β) and IL-7 levels. Findings suggest that iron deficiency may exacerbate lung lesions by altering T cell subsets and cytokine profiles.

Mucosal-associated invariant T cells are highly conserved innate-like T cells in mammals recognized for their high baseline frequency in human blood and cytotoxic effector functions during infectious diseases, autoimmunity, and cancer. While the majority of these cells express a conserved CD8αβ+ TRAV1-2 T cell receptor recognizing microbially-derived Vitamin B2 intermediates presented by the evolutionarily conserved major histocompatibility complex I-related molecule, MR1, there is an emerging appreciation for diverse subsets that may be selected for in humans with distinct functions, including subpopulations that co-express CD4. Prior work has not examined T cell receptor (TCR) heterogeneity in CD4 + MAIT cells, largely due to bias of identifying human MAIT cells as CD8 + TRAV1-2 + cells. In this study, we adopted an unbiased single-cell TCR-sequencing approach of total MR1-5-OP-RU-tetramer-reactive T cells and discovered that CD4 + MAIT cells express highly diverse TRAV1-2 negative TCRs. To specifically characterize this TCR repertoire, we analyzed VDJ sequences of single MR1-5-OP-RU tetramer + MAIT cells across two datasets and identified distinct TCR usage among CD4 + MAIT cells including TRAV21, TRAV8 (TRAV8-1, TRAV8-2, TRAV8-3), and TRAV12 families (TRAV12-2, TRAV12-3), as well as more variable J chain and CDR3 sequences. Non-TRAV1-2 MAIT cell TCRs were also enriched after in vitro expansion, including with Mycobacterial tuberculosis . These results indicate that mature human CD4 + MAIT cells adopt distinct TCR usage from the canonical TRAV1-2 + CD8 + subset and suggest that alternative MR1 ligands in addition to riboflavin intermediates may select them.

Mucosa-associated invariant T (MAIT) cells are a large population of unconventional T cells widely distributed in the human gastrointestinal tract. Their homing to the gut is central to maintaining mucosal homeostasis and immunity. This review discusses the potential mechanisms that guide MAIT cells to the intestinal mucosa during homeostasis and inflammation, emphasizing the roles of chemokines, chemokine receptors, and tissue adhesion molecules. The potential influence of the gut microbiota on MAIT cell homing to different regions of the human gut is also discussed. Last, we introduce how organoid technology offers a potentially valuable approach to advance our understanding of MAIT cell tissue homing by providing a more physiologically relevant model that mimics the human gut tissue. These models may enable a detailed investigation of the gut-specific homing mechanisms of MAIT cells. By understanding the regulation of MAIT cell homing to the human gut, potential avenues for therapeutic interventions targeting gut inflammatory conditions such as inflammatory bowel diseases (IBD) may emerge.

Tobacco smoking is prevalent across the world and causes numerous diseases. Cigarette smoke (CS) compromises immunity, yet little is known of the components of CS that impact T cell function. MR1 is a ubiquitous molecule that presents bacterial metabolites to MAIT cells, which are highly abundant in the lungs. Using in silico, cellular, and biochemical approaches, we identified components of CS that bind MR1 and impact MR1 cell surface expression. Compounds, including nicotinaldehyde, phenylpropanoid, and benzaldehyde-related scaffolds, bound within the A' pocket of MR1. CS inhibited MAIT cell activation, ex vivo, via TCR-dependent and TCR-independent mechanisms. Chronic CS exposure altered MAIT cell phenotype and function and attenuated MAIT cell responses to influenza A virus infection in vivo. MR1-deficient mice were partially protected from the development of chronic obstructive pulmonary disease (COPD) features that were associated with CS exposure. Thus, CS can impair MAIT cell function by diverse mechanisms, and potentially contribute to infection susceptibility and disease exacerbations.

Mucosal-Associated Invariant T (MAIT) cells, which bridge innate and adaptive immunity, have emerged as an important player in viral infections despite their inability to directly recognize viral antigens. This review provides a comprehensive analysis of MAIT cell responses across different viral infections, revealing consistent patterns in their behavior and function. We discuss the dynamics of MAIT cells during various viral infections, including changes in their frequency, activation status, and functional characteristics. Particular attention is given to emerging strategies for MAIT-cell-targeted vaccine development, including the use of MR1 ligands as mucosal adjuvants and the activation of MAIT cells through viral vectors and mRNA vaccines. Current knowledge of MAIT cell biology in viral infections provides promising approaches for harnessing their functions in vaccine development.

Mucosal-associated invariant T (MAIT) cells exhibit significant potential in the assessment of tumor development and immunotherapy. However, there is currently no convenient and efficient method to analyze the quantitative changes of MAIT cells during cancer development and treatment, which has not been extensively studied. Here, we report an electrochemical biosensor designed to efficiently monitor MAIT cells in peripheral blood by simultaneously recognizing Vα7.2 and CD161 on MAIT cells. Natural red blood cell membrane, tetrahedral DNA nanostructure, and modified nanometal framework are selected as antifouling coating, antibody scaffold, and electrochemical probe, respectively. Owing to the synergistic effects of these materials, the biosensor achieves robust antifouling ability while maintaining excellent detection performance using rapid differential pulse voltammetry. We show a decrease in the number of MAIT cells in peripheral blood associated with aging and the development of mucosa-associated tumors. Our research has prospects in assessing the degree of malignancy of tumors, distinguishing immunotherapy responses in patients, reducing costs, and promoting the transformation of electrochemical sensing technology into clinical settings.

Mucosal-associated invariant T (MAIT) cells, a type of T lymphocytes with innate-like characteristics, are crucial in bridging innate and adaptive immunity. When activated, MAIT cells release various inflammatory molecules and swiftly respond to antigens. Notably, numerous studies highlight the significant impact of MAIT cells on tumors and various immune disorders by influencing the immune microenvironment. Oral lichen planus (OLP) is an immune-mediated inflammatory condition mainly involving T lymphocytes. Previous research primarily focused on T cells alone, neglecting the broader immune environment. However, there is a current growing recognition of the complex interactions among multiple immune cells and inflammatory factors in patients with OLP. This immune microenvironment comprises T lymphocytes, fibroblasts, keratinocytes, dendritic cells, macrophages, inflammation-related cytokines, and chemokines, orchestrating intricate interactions that contribute to OLP initiation and persistence. Therefore, this review consolidates current research on the interplay between MAIT cells and other immune cells within the OLP microenvironment. We also delve into potential mechanisms through which MAIT cells regulate inflammation in patients with OLP, aiming to further explore the role of MAIT cells in these patients.

The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosal-associated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1*01 and/or MR1*02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3-5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.

The CD8 co-receptor exists as both an αα homodimer, expressed on subsets of specialized lymphoid cells, and as an αβ heterodimer, which is the canonical co-receptor on cytotoxic T-cells, tuning TCR thymic selection and antigen-reactivity in the periphery. However, the biophysical parameters governing human CD8αβ interactions with classical MHC class I (MHCI) and unconventional MHC-like molecules have not been determined. Using hetero-dimerized Fc-fusions to generate soluble human CD8αβ, we demonstrate similar weak binding affinity to multiple different MHCI alleles compared with CD8αα. We observed that both forms of CD8 bound to certain alleles with stronger affinity than others and found that the affinity of thymically selected TCRs was inversely associated with the affinity of the CD8 co-receptor for the different alleles. We further demonstrated the binding of CD8αα and CD8αβ to the unconventional MHC-like molecule, MHCI-related protein 1, with a similar affinity as for classical MHCI, but no interaction was observed for the other unconventional MHC-like molecules, CD1a, b, c, or d. In summary, this is the first characterization of human CD8αβ binding to MHCI and MHC-like molecules that revealed an intriguing relationship between CD8 binding affinity for different MHCI alleles and the selection of TCRs in the thymus.

Mucosal-associated invariant T (MAIT) cells are known for their rapid effector functions and antibacterial immune protection. Here, we define the plasticity of interferon-γ (IFN-γ)-producing MAIT1 and interleukin-17A (IL-17A)-producing MAIT17 cell subsets in vivo. Whereas T-bet+ MAIT1 cells remained stable in all experimental settings, after adoptive transfer or acute Legionella or Francisella infection, RORγt+ MAIT17 cells could undergo phenotypic and functional conversion into both RORγt+T-bet+ MAIT1/17 and RORγt-T-bet+ MAIT1 cells. This plasticity ensured that MAIT17 cells played a dominant role in generating antibacterial MAIT1 responses in mucosal tissues. Single-cell transcriptomics revealed that MAIT17-derived MAIT1 cells were distinct from canonical MAIT1 cells yet could migrate out of mucosal tissues to contribute to the global MAIT1 pool in subsequent systemic infections. Human IL-17A-secreting MAIT cells also showed similar functional plasticity. Our findings have broad implications for understanding the role of MAIT cells in combatting infections and their potential utility in MAIT cell-targeted vaccines.

The major histocompatibility complex class I related protein (MR1) presents microbially derived vitamin B2 precursors to mucosal-associated invariant T (MAIT) cells. MR1 can also present other metabolites to activate MR1-restricted T cells expressing more diverse T cell receptors (TCRs), some with anti-tumor reactivity. However, knowledge of the range of the antigen(s) that can activate diverse MR1-reactive T cells remains incomplete. Here, we identify pyridoxal (vitamin B6) as a naturally presented MR1 ligand using unbiased mass spectrometry analyses of MR1-bound metabolites. Pyridoxal, and the related compound, pyridoxal 5-phosphate bound to MR1 and enabled cell surface upregulation of wild type MR1*01 and MR1 expressing the Arg9His polymorphism associated with the MR1*04 allotype in a manner dependent on Lys43-mediated Schiff-base formation. Crystal structures of MR1*01 in complex with pyridoxal and pyridoxal 5-phosphate showed how these ligands were accommodated within the A-pocket of MR1. T cell lines transduced with the 7.G5 TCR, which has reported "pan-cancer" specificity, were specifically activated by pyridoxal presented by antigen-presenting cells expressing MR1*01 and MR1 allotypes bearing the less common Arg9His polymorphism. 7.G5 T cells also recognized, to a lesser extent, pyridoxal 5-phosphate and, importantly, recognition of both vitamers was blocked by an anti-MR1 antibody. 7.G5 TCR reactivity toward pyridoxal was enhanced when presented by the Arg9His polymorphism-bearing MR1 allotypes. Vitamin B6, and vitamers thereof, have been associated with various cancers, and here we describe a link between this ligand, MR1, and its allomorphs, and the pan-cancer 7.G5 TCR. This work identifies an MR1 ligand that can activate a diverse MR1-restricted TCR.

Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T (γδT) cells, comprise distinct T-bet+, IFN-γ+ and RORγt+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, γδT, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, γδT1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7. These markers could be further upregulated upon exposure to retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, γδT1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-γ-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-γ and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-γ- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.

Mucosal-associated invariant T (MAIT) cells are a predominant subset of innate-like T cells in humans, characterized by diverse gene expression profiles and functional capabilities. However, the factors influencing the transcriptomes and effector functions of MAIT cells, particularly at mucosal barriers, remain largely unclear.

In this study, we employed single-cell RNA sequencing (scRNA-seq) and functional assays to investigate the transcriptomic and functional characteristics of intestinal MAIT cells in mouse models during aging. We also extended scRNA-seq analysis to human intestinal MAIT cells to compare their gene expression patterns with those observed in aged mice.

Our findings demonstrated that the transcriptomes and functional capabilities of intestinal MAIT cells shifted from MAIT17 to MAIT1 profiles with aging in mouse models, with notable changes in the production of cytotoxic molecules. Further scRNA-seq analysis of human intestinal MAIT cells revealed a segregation into MAIT1 and MAIT17 subsets, displaying gene expression patterns that mirrored those seen in aged mouse models. The transcription factor RORγt was expressed in both MAIT1 and MAIT17 cells, acting to repress IFNγ production while promoting IL17 expression. Moreover, reduced expression of RORC and Il17A was correlated with poorer survival outcomes in colorectal cancer patients.

These results suggest that aging induces a functional shift between MAIT1 and MAIT17 cells, which may be influenced by transcriptional regulators like RORγt. The observed alterations in MAIT cell activity could potentially impact disease prognosis, particularly in colorectal cancer. This study provides new insights into the dynamics of MAIT cell responses at mucosal barriers, highlighting possible therapeutic targets for modulating MAIT cell functions in aging and disease.

Optimal control of microbial infections requires mucosal-associated invariant T (MAIT) cells. People living with HIV (PWH) on antiretroviral therapy (ART) can be divided into 2 groups: immune responders (IR) who recover or retain CD4 T cell numbers, and immune non-responders (INR) who do not. Compared to IR, INR have fewer MAIT cells and increased systemic inflammation and microbial translocation, but how these factors affect MAIT cells is unknown.

MAIT cells from IR, INR, and from controls without HIV were enumerated and characterized by flow cytometry. To determine the links among MAIT cells, inflammation, and microbial translocation, the correlations of MAIT cell numbers to previously published soluble inflammatory markers and plasma microbial genetic sequences were assessed by Spearman analysis. In vitro assays were used to support our findings.

MAIT cell numbers were significantly negatively correlated with levels of IL-6 and IP-10 (markers of inflammation); CD14, LPS, and FABP2 (markers of microbial translocation); and with abundance of Serratia and other Proteobacteria genetic sequences in plasma. In a separate analysis of PWH on ART receiving the IL-6 receptor antagonist tocilizumab (TCZ), we found that blocking IL-6 signaling with TCZ increased IL-7 receptor expression on MAIT cells and reduced plasma IL-7 levels, consistent with improved uptake of IL-7 in vivo.

Our findings suggest inflammation and microbial translocation in PWH on ART lead to a loss of MAIT cells via impaired IL-7 responsiveness, resulting in further increased microbial translocation and inflammation.

Immunoglobulin A (IgA) is the most abundantly produced antibody in humans. IgA is a unique class of immunoglobulin due to its multiple molecular forms, and a defining difference between the two subclasses: IgA1 has a long hinge-region that is heavily O-glycosylated, whereas the IgA2 hinge-region is shorter but resistant to bacterial proteases prevalent at mucosal sites. IgA is essential for immune homeostasis and education. Mucosal IgA plays a crucial role in maintaining the integrity of the mucosal barrier by immune exclusion of pathobionts while facilitating colonization with certain commensals; a large part of the gut microbiota is coated with IgA. In the circulation, monomeric IgA that has not been engaged by antigen plays a discrete role in dampening inflammatory responses. Protective and harmful roles of IgA have been studied over several decades, but a new understanding of the complex role of this immunoglobulin in health and disease has been provided by recent studies. Here, we discuss the physiological and pathological roles of IgA with a special focus on the gut, kidneys, and autoimmunity. We also discuss new IgA-based therapeutic approaches.

It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms.

Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 )] relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes [ CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 )] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies.

These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.

Tuberculosis (TB) is still an urgent global public health problem. Notably, mucosal-associated invariant T (MAIT) cells play an important role in early anti-TB immune response. Targeted control of them may be an effective method to improve vaccine efficacy and TB treatment. However, the biology and signal regulation mechanisms of MAIT cells in TB patients are still poorly understood. Previous studies have been limited by the lack of reagents to specifically identify MAIT cells. In addition, the use of alternative markers may subsume non-MAIT cell into MAIT cell populations. In this study, the human MR1 tetramer which can specifically identify MAIT cells was used to further explore the effect and mechanism of MAIT cells in anti-TB immune response. Our results showed that the tetramer+ MAIT cells in peripheral blood of TB patients were mainly CD8+ or CD4-CD8- cells, and very few were CD4+ cells. After BCG infecting autologous antigen-presenting cells, MAIT cells in patients produced significantly higher levels of cytokines, lysis and proliferation compared with healthy controls. After suppression of mTORC1 by the mTORC1-specific inhibitor rapamycin, the immune response of MAIT cells in patients was significantly reduced. This study demonstrates that peripheral blood tetramer+ MAIT cells from TB patients have significant anti-TB immune effect, which is regulated by mTORC1. This could provide ideas and potential therapeutic targets for the development of novel anti-TB immunotherapy.

The lungs face constant environmental challenges from harmless molecules, airborne pathogens and harmful agents that can damage the tissue. The lungs' immune system includes numerous tissue-resident lymphocytes that contribute to maintain tissue homeostasis and to the early initiation of immune responses. Amongst tissue-resident lymphocytes, Mucosal Associated Invariant T (MAIT) cells are present in human and murine lungs and emerging evidence supports their contribution to immune responses during infections, chronic inflammatory disorders and cancer. This review explores the mechanisms underpinning MAIT cell functions in the airways, their impact on lung immunity and the potential for targeting pulmonary MAIT cells in a therapeutic context.

Presentation of metabolites by the major histocompatibility complex class I-related protein 1 (MR1) molecule to mucosal-associated invariant T cells is impaired during herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. This is surprising given these viruses do not directly synthesise MR1 ligands. We have previously identified several HSV proteins responsible for rapidly downregulating the intracellular pool of immature MR1, effectively inhibiting new surface antigen presentation, while preexisting ligand-bound mature MR1 is unexpectedly upregulated by HSV-1. Using flow cytometry, immunoblotting, and high-throughput fluorescence microscopy, we demonstrate that the endocytosis of surface MR1 is impaired during HSV infection and that internalized molecules accumulate in EEA1-labeled early endosomes, avoiding degradation. We establish that the short MR1 cytoplasmic tail is not required for HSV-1-mediated downregulation of immature molecules; however it may play a role in the retention of mature molecules on the surface and in early endosomes. We also determine that the HSV-1 US3 protein, the shorter US3.5 kinase and the full-length HSV-2 homolog, all predominantly target mature surface rather than total MR1 levels. We propose that the downregulation of intracellular and cell surface MR1 molecules by US3 and other HSV proteins is an immune-evasive countermeasure to minimize the effect of impaired MR1 endocytosis, which might otherwise render infected cells susceptible to MR1-mediated killing by mucosal-associated invariant T cells.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αβT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αβT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.

T cell activation is governed through T cell receptors (TCRs), heterodimers of two sequence-variable chains (often an α and β chain) that synergistically recognize antigen fragments presented on cell surfaces. Despite this, there only exist repositories dedicated to collecting single-chain, not paired-chain, TCR sequence data. We addressed this gap by creating the Observed TCR Space (OTS) database, a source of consistently processed and annotated, full-length, paired-chain TCR sequences. Currently, OTS contains 5.35 million redundant (1.63 million non-redundant), predominantly human sequences from across 50 studies and at least 75 individuals. Using OTS, we identify pairing biases, public TCRs, and distinct chain coherence patterns relative to antibodies. We also release a paired-chain TCR language model, providing paired embedding representations and a method for residue in-filling conditional on the partner chain. OTS will be updated as a central community resource and is freely downloadable and available as a web application.

The "innate-like" T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species.

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize microbial riboflavin pathway metabolites presented by evolutionarily conserved MR1 molecules. We explored the human MAIT cell compartment across organ donor-matched blood, barrier, and lymphoid tissues. MAIT cell population size was donor dependent with distinct tissue compartmentalization patterns and adaptations: Intestinal CD103+ resident MAIT cells presented an immunoregulatory CD39highCD27low profile, whereas MAIT cells expressing NCAM1/CD56 dominated in the liver and exhibited enhanced effector capacity with elevated response magnitude and polyfunctionality. Both intestinal CD39high and hepatic CD56+ adaptations accumulated with donor age. CD56+ MAIT cells displayed limited T cell receptor-repertoire breadth, elevated MR1 binding, and a transcriptional profile skewed toward innate activation pathways. Furthermore, CD56 was dynamically up-regulated to a persistent steady-state equilibrium after exposure to antigen or IL-7. In summary, we demonstrate functional heterogeneity and tissue site adaptation in resident MAIT cells across human barrier tissues with distinct regulatory and effector signatures.

Mucosal-associated invariant T (MAIT) cells assume pivotal roles in numerous autoimmune inflammatory maladies. However, scant knowledge exists regarding their involvement in the pathological progression of oral lichen planus (OLP). The focus of our study was to explore whether MAIT cells were altered across distinct clinical types of OLP.

The frequency, phenotype, and partial functions of MAIT cells were performed by flow cytometry, using peripheral blood from 18 adults with non-erosive OLP and 22 adults with erosive OLP compared with 15 healthy adults. We also studied the changes in MAIT cells in 15 OLP patients receiving and 10 not receiving corticosteroids. Surface proteins including CD4, CD8, CD69, CD103, CD38, HLA-DR, Tim-3, Programmed Death Molecule-1 (PD-1), and related factors released by MAIT cells such as Granzyme B (GzB), interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-17A, and IL-22 were detected.

Within non-erosive OLP patients, MAIT cells manifested an activated phenotype, evident in an elevated frequency of CD69+ CD38+ MAIT cells (p < 0.01). Conversely, erosive OLP patients displayed an activation and depletion phenotype in MAIT cells, typified by elevated CD69 (p < 0.01), CD103 (p < 0.05), and PD-1 expression (p < 0.01). Additionally, MAIT cells exhibited heightened cytokine production, encompassing GzB, IFN-γ, and IL-17A in erosive OLP patients. Notably, the proportion of CD103+ MAIT cells (p < 0.05) and GzB secretion (p < 0.01) by MAIT cells diminished, while the proportion of CD8+ MAIT cells (p < 0.05) rose in OLP patients with corticosteroid therapy.

MAIT cells exhibit increased pathogenicity and pro-inflammatory capabilities in OLP. Corticosteroid therapy influences the expression of certain phenotypes and functions of MAIT cells in the peripheral blood of OLP patients.