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Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Recent discoveries have demonstrated that tissue-resident lymphocyte subsets, comprised of innate lymphoid cells (ILCs) and unconventional T cells, have vital roles in the initiation of primary antiviral responses. Via direct and indirect mechanisms, ILCs and unconventional T cell subsets play a critical role in the ability of the immune system to mount an effective antiviral response through potent early cytokine production. In this review, we will summarize the current knowledge of tissue-resident lymphocytes during initial viral infection and evaluate their redundant or nonredundant contributions to host protection or virus-induced pathology.

Unlike conventional major histocompatibility complex (MHC) class I and II molecules reactive T cells, the unconventional T cell subpopulations recognize various non-polymorphic antigen-presenting molecules and are typically characterized by simplified patterns of T cell receptors (TCRs), rapid effector responses and 'public' antigen specificities. Dissecting the recognition patterns of the non-MHC antigens by unconventional TCRs can help us further our understanding of the unconventional T cell immunity. The small size and irregularities of the released unconventional TCR sequences are far from highquality to support systemic analysis of unconventional TCR repertoire. Here we present UcTCRdb, a database that contains 669,900 unconventional TCRs collected from 34 corresponding studies in humans, mice, and cattle. In UcTCRdb, users can interactively browse TCR features of different unconventional T cell subsets in different species, search and download sequences under different conditions. Additionally, basic and advanced online TCR analysis tools have been integrated into the database, which will facilitate the study of unconventional TCR patterns for users with different backgrounds. UcTCRdb is freely available at http://uctcrdb.cn/. [ABSTRACT FROM AUTHOR]

Summary: The heterogeneous pool of tissue-resident lymphocytes in solid organs mediates infection responses and supports tissue integrity and repair. Their vital functions in normal physiology suggest an important role in solid organ transplantation; however, their detailed examination in this context has not been performed. Here, we report the fate of multiple lymphocyte subsets, including T, B, and innate lymphoid cells, after murine liver and heart transplantation. In major histocompatibility complex (MHC)-matched transplantation, donor lymphocytes are retained in liver grafts and peripheral lymphoid organs of heart and liver transplant recipients. In MHC-mismatched transplantation, increased infiltration of the graft by recipient cells and depletion of donor lymphocytes occur, which can be prevented by removal of recipient T and B cells. Recipient lymphocytes fail to recreate the native organs’ phenotypically diverse tissue-resident lymphocyte composition, even in MHC-matched models. These post-transplant changes may leave grafts vulnerable to infection and impair long-term graft function.

The immune system has coevolved with extensive microbial communities living on barrier sites that are collectively known as the microbiota. It is increasingly clear that microbial antigens and metabolites engage in a constant dialogue with the immune system, leading to microbiota-specific immune responses that occur in the absence of inflammation. This form of homeostatic immunity encompasses many arms of immunity, including B cell responses, innate-like T cells, and conventional T helper and T regulatory responses. In this review we summarize known examples of innate-like T cell and adaptive immunity to the microbiota, focusing on fundamental aspects of commensal immune recognition across different barrier sites. Furthermore, we explore how this cross talk is established during development, emphasizing critical temporal windows that establish long-term immune function. Finally, we highlight how dysregulation of immunity to the microbiota can lead to inflammation and disease, and we pinpoint outstanding questions and controversies regarding immune system–microbiota interactions. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are a population of innate-like T cells that utilize a semi-invariant T cell receptor (TCR) α chain and are restricted by the highly conserved antigen presenting molecule MR1. MR1 presents microbial riboflavin biosynthesis derived metabolites produced by bacteria and fungi. Consistent with their ability to sense ligands derived from bacterial sources, MAIT cells have been associated with the immune response to a variety of bacterial infections, such as Mycobacterium spp., Salmonella spp. and Escherichia coli. To date, MAIT cells have been studied in humans, non-human primates and mice. However, they have only been putatively identified in cattle by PCR based methods; no phenotypic or functional analyses have been performed. Here, we identified a MAIT cell population in cattle utilizing MR1 tetramers and high-throughput TCR sequencing. Phenotypic analysis of cattle MAIT cells revealed features highly analogous to those of MAIT cells in humans and mice, including expression of an orthologous TRAV1-TRAJ33 TCR α chain, an effector memory phenotype irrespective of tissue localization, and expression of the transcription factors PLZF and EOMES. We determined the frequency of MAIT cells in peripheral blood and multiple tissues, finding that cattle MAIT cells are enriched in mucosal tissues as well as in the mesenteric lymph node. Cattle MAIT cells were responsive to stimulation by 5-OP-RU and riboflavin biosynthesis competent bacteria in vitro. Furthermore, MAIT cells in milk increased in frequency in cows with mastitis. Following challenge with virulent Mycobacterium bovis, a causative agent of bovine tuberculosis and a zoonosis, peripheral blood MAIT cells expressed higher levels of perforin. Thus, MAIT cells are implicated in the immune response to two major bacterial infections in cattle. These data suggest that MAIT cells are functionally highly conserved and that cattle are an excellent large animal model to study the role of MAIT cells in important zoonotic infections.

Mucosal-associated invariant T (MAIT) cells are a population of innate-like T cells that utilize a semi-invariant T cell receptor (TCR) α chain and are restricted by the highly conserved antigen presenting molecule MR1. MR1 presents microbial riboflavin biosynthesis derived metabolites produced by bacteria and fungi. Consistent with their ability to sense ligands derived from bacterial sources, MAIT cells have been associated with the immune response to a variety of bacterial infections, such as Mycobacterium spp., Salmonella spp. and Escherichia coli. To date, MAIT cells have been studied in humans, non-human primates and mice. However, they have only been putatively identified in cattle by PCR based methods; no phenotypic or functional analyses have been performed. Here, we identified a MAIT cell population in cattle utilizing MR1 tetramers and high-throughput TCR sequencing. Phenotypic analysis of cattle MAIT cells revealed features highly analogous to those of MAIT cells in humans and mice, including expression of an orthologous TRAV1-TRAJ33 TCR α chain, an effector memory phenotype irrespective of tissue localization, and expression of the transcription factors PLZF and EOMES. We determined the frequency of MAIT cells in peripheral blood and multiple tissues, finding that cattle MAIT cells are enriched in mucosal tissues as well as in the mesenteric lymph node. Cattle MAIT cells were responsive to stimulation by 5-OP-RU and riboflavin biosynthesis competent bacteria in vitro. Furthermore, MAIT cells in milk increased in frequency in cows with mastitis. Following challenge with virulent Mycobacterium bovis , a causative agent of bovine tuberculosis and a zoonosis, peripheral blood MAIT cells expressed higher levels of perforin. Thus, MAIT cells are implicated in the immune response to two major bacterial infections in cattle. These data suggest that MAIT cells are functionally highly conserved and that cattle are an excellent large animal model to study the role of MAIT cells in important zoonotic infections. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, both in circulation and especially in some tissues such as the liver. Secondly is the discovery of a ligand that has uncovered their microbial targets, and also allowed for the development of tools to accurately track the cells in both humans and mice. Finally, it appears that the cells not only have a diverse range of functions but also are sensitive to a range of inflammatory triggers that can enhance or even bypass T cell receptor–mediated signals—substantially broadening their likely impact in health and disease. In this review we discuss how MAIT cells display antimicrobial, homeostatic, and amplifier roles in vivo, and how this may lead to protection and potentially pathology. [ABSTRACT FROM AUTHOR]

Highlights • The non-classical MHC pathways are important in skin immunity. • CD1 proteins are involved in skin inflammatory diseases. • γδ T cells are key players in skin immunity and tissue homeostasis. • Other non-classical MHC restricted T cells may contribute to skin immunity. • Targeting non-classical T cells has potential in inflammatory skin disease therapy. Abstract The immune network controls homeostasis and inflammation of the skin. Immune cells use their antigen receptors to respond to a wide range of insults originating from microbes and allergens. T cells, which are key effector cells in the immune system, engage their T cell receptors (TCRs) to recognize self and foreign antigens in the context of classical major histocompatibility complex (MHC) molecules, MHC-like CD1 proteins, or MHC class I-related molecules. Recently, increasing evidence has demonstrated that T cells activated by non-canonical antigens are important in skin diseases. This review focuses on recent studies examining the roles of non-classical antigen-presenting molecules and their reactive T cells in the skin immune system. Additionally, we describe the types of ligands that activate these unconventional T cells through the non-classical MHC pathway. Finally, we highlight recent advances in the understanding of the physiological functions of non-classical T cells in the skin. Further investigation may result in the development of new therapeutic strategies for treating immune-related skin diseases. [ABSTRACT FROM AUTHOR]

Abstract: Mucosal‐associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non‐lineage‐specific (surrogate) markers such as anti‐TRAV1‐2, CD161, IL‐18Rα and CD26. The development of MR1‐Ag tetramers now permits the specific identification of MAIT cells based on T‐cell receptor specificity. Here, we compare these approaches for identifying MAIT cells and show that surrogate markers are not always accurate in identifying these cells, particularly the CD4+ fraction. Moreover, while all MAIT cell subsets produced comparable levels of IFNγ, TNF and IL‐17A, the CD4+ population produced more IL‐2 than the other subsets. In a human ontogeny study, we show that the frequencies of most MR1 tetramer+ MAIT cells, with the exception of CD4+ MAIT cells, increased from birth to about 25 years of age and declined thereafter. We also demonstrate a positive association between the frequency of MAIT cells and other unconventional T cells including Natural Killer T (NKT) cells and Vδ2+ γδ T cells. Accordingly, this study demonstrates that MAIT cells are phenotypically and functionally diverse, that surrogate markers may not reliably identify all of these cells, and that their numbers are regulated in an age‐dependent manner and correlate with NKT and Vδ2+ γδ T cells. [ABSTRACT FROM AUTHOR]

Besides the central role of classical Major Histocompatibility Complex (MHC) class Ia-restricted conventional Cluster of Differentiation 8 (CD8) T cells in antiviral host immune response, the amphibian Xenopus laevis critically rely on MHC class I-like (mhc1b10.1.L or XNC10)-restricted innate-like (i)T cells (iVα6 T cells) to control infection by the ranavirus Frog virus 3 (FV3). To complement and extend our previous reverse genetic studies showing that iVα6 T cells are required for tadpole survival, as well as for timely and effective adult viral clearance, we examined the conditions and kinetics of iVα6 T cell response against FV3. Using a FV3 knock-out (KO) growth-defective mutant, we found that upregulation of the XNC10 restricting class I-like gene and the rapid recruitment of iVα6 T cells depend on detectable viral replication and productive FV3 infection. In addition, by in vivo depletion with XNC10 tetramers, we demonstrated the direct antiviral effector function of iVα6 T cells. Notably, the transitory iVα6 T cell defect delayed innate interferon and cytokine gene response, resulting in long-lasting negative inability to control FV3 infection. These findings suggest that in Xenopus and likely other amphibians, an immune surveillance system based on the early activation of iT cells by non-polymorphic MHC class-I like molecules is important for efficient antiviral immune response.

Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Recent discoveries have demonstrated that tissue-resident lymphocyte subsets, comprised of innate lymphoid cells (ILCs) and unconventional T cells, have vital roles in the initiation of primary antiviral responses. Via direct and indirect mechanisms, ILCs and unconventional T cell subsets play a critical role in the ability of the immune system to mount an effective antiviral response through potent early cytokine production. In this review, we will summarize the current knowledge of tissue-resident lymphocytes during initial viral infection and evaluate their redundant or nonredundant contributions to host protection or virus-induced pathology.

MAIT cells are one representative of a group of related unconventional or pre-set T cells, and are particularly abundant in humans. While these unconventional T cell types, which also include populations of Vδ2 cells and iNKT cells, recognise quite distinct ligands, they share functional features including the ability to sense "danger" by integration of cytokine signals. Since such signals are common to many human pathologies, activation of MAIT cells in particular has been widely observed. In this review we will discuss recent trends in these data, for example the findings from patients with Covid-19 and responses to novel vaccines. Covid-19 is an example where MAIT cell activation has been correlated with disease severity by several groups, and the pathways leading to activation are being clarified, but the overall role of the cells in vivo requires further exploration. Given the potential wide functional responsiveness of these cells, which ranges from tissue repair to cytotoxicity, and likely impacts on the activity of many other cell populations, defining the role of these cells - not only as sensitive biomarkers but also as mediators - across human disease remains an important task. [ABSTRACT FROM AUTHOR]

Unlike conventional major histocompatibility complex (MHC) class I and II molecules reactive T cells, the unconventional T cell subpopulations recognize various non-polymorphic antigen-presenting molecules and are typically characterized by simplified patterns of T cell receptors (TCRs), rapid effector responses and 'public' antigen specificities. Dissecting the recognition patterns of the non-MHC antigens by unconventional TCRs can help us further our understanding of the unconventional T cell immunity. The small size and irregularities of the released unconventional TCR sequences are far from high-quality to support systemic analysis of unconventional TCR repertoire. Here we present UcTCRdb, a database that contains 669,900 unconventional TCRs collected from 34 corresponding studies in humans, mice, and cattle. In UcTCRdb, users can interactively browse TCR features of different unconventional T cell subsets in different species, search and download sequences under different conditions. Additionally, basic and advanced online TCR analysis tools have been integrated into the database, which will facilitate the study of unconventional TCR patterns for users with different backgrounds. UcTCRdb is freely available at http://uctcrdb.cn/., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dou, Shan and Zhang.)

The heterogeneous pool of tissue-resident lymphocytes in solid organs mediates infection responses and supports tissue integrity and repair. Their vital functions in normal physiology suggest an important role in solid organ transplantation; however, their detailed examination in this context has not been performed. Here, we report the fate of multiple lymphocyte subsets, including T, B, and innate lymphoid cells, after murine liver and heart transplantation. In major histocompatibility complex (MHC)-matched transplantation, donor lymphocytes are retained in liver grafts and peripheral lymphoid organs of heart and liver transplant recipients. In MHC-mismatched transplantation, increased infiltration of the graft by recipient cells and depletion of donor lymphocytes occur, which can be prevented by removal of recipient T and B cells. Recipient lymphocytes fail to recreate the native organs' phenotypically diverse tissue-resident lymphocyte composition, even in MHC-matched models. These post-transplant changes may leave grafts vulnerable to infection and impair long-term graft function. [Display omitted] • The liver contains diverse, transplantable tissue-resident lymphocyte populations • Donor lymphocytes are deleted after MHC-mismatched transplantation by recipient T and B cells • Graft-infiltrating cells do not recreate a native organ's lymphocyte composition Prosser et al. characterize tissue-resident lymphocytes in the liver and map the changes to the donor and recipient lymphocyte compartment after liver and heart transplantation in mice. The graft becomes significantly altered in comparison to a native organ, with implications for infection control and graft function. [ABSTRACT FROM AUTHOR]

Simple Summary: Unconventional T cells have recently come under intense scrutiny because of their innate-like effector functions and unique antigen specificity, suggesting their potential importance in antitumor immunity. MAIT cells, one such population of unconventional T cell, have been shown to significantly influence bacterial infections, parasitic and fungal infections, viral infections, autoimmune and other inflammatory diseases, and, as discussed thoroughly in this review, various cancers. This review aims to merge accumulating evidence, tease apart the complexities of MAIT cell biology in different malignancies, and discuss how these may impact clinical outcomes. While it is clear that MAIT cells can impact the tumor microenvironment, the nature of these interactions varies depending on the type of cancer, subset of MAIT cell, patient demographic, microbiome composition, and the type of therapy administered. This review examines the impact of these variables on MAIT cells and discusses outstanding questions within the field. A recent boom in mucosal-associated invariant T (MAIT) cell research has identified relationships between MAIT cell abundance, function, and clinical outcomes in various malignancies. As they express a variety of immune checkpoint receptors and ligands, and possess strong cytotoxic functions, MAIT cells are an attractive new subject in the field of tumor immunology. MAIT cells are a class of innate-like T cells that express a semi-invariant T cell antigen receptor (TCR) that recognizes microbially derived non-peptide antigens presented by the non-polymorphic MHC class-1 like molecule, MR1. In this review, we outline the current (and often contradictory) evidence exploring MAIT cell biology and how MAIT cells impact clinical outcomes in different human cancers, as well as what role they may have in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Besides the central role of classical Major Histocompatibility Complex (MHC) class Ia-restricted conventional Cluster of Differentiation 8 (CD8) T cells in antiviral host immune response, the amphibian Xenopus laevis critically rely on MHC class I-like (mhc1b10.1.L or XNC10)-restricted innate-like (i)T cells (iVα6 T cells) to control infection by the ranavirus Frog virus 3 (FV3). To complement and extend our previous reverse genetic studies showing that iVα6 T cells are required for tadpole survival, as well as for timely and effective adult viral clearance, we examined the conditions and kinetics of iVα6 T cell response against FV3. Using a FV3 knock-out (KO) growth-defective mutant, we found that upregulation of the XNC10 restricting class I-like gene and the rapid recruitment of iVα6 T cells depend on detectable viral replication and productive FV3 infection. In addition, by in vivo depletion with XNC10 tetramers, we demonstrated the direct antiviral effector function of iVα6 T cells. Notably, the transitory iVα6 T cell defect delayed innate interferon and cytokine gene response, resulting in long-lasting negative inability to control FV3 infection. These findings suggest that in Xenopus and likely other amphibians, an immune surveillance system based on the early activation of iT cells by non-polymorphic MHC class-I like molecules is important for efficient antiviral immune response. [ABSTRACT FROM AUTHOR]