Explore the vast range of titles available.

In recent years, a population of unconventional T cells called ‘mucosal-associated invariant T cells’ (MAIT cells) has captured the attention of immunologists and clinicians due to their abundance in humans, their involvement in a broad range of infectious and non-infectious diseases and their unusual specificity for microbial riboflavin-derivative antigens presented by the major histocompatibility complex (MHC) class I–like protein MR1. MAIT cells use a limited T cell antigen receptor (TCR) repertoire with public antigen specificities that are conserved across species. They can be activated by TCR-dependent and TCR-independent mechanisms and exhibit rapid, innate-like effector responses. Here we review evidence showing that MAIT cells are a key component of the immune system and discuss their basic biology, development, role in disease and immunotherapeutic potential. Godfrey and colleagues review the basic biology, development, role in disease and immunotherapeutic potential of MAIT cells.

Natural Killer T (NKT) cells are a functionally diverse population that recognizes lipid‐based antigens in association with the antigen‐presenting molecule CD1d. Here, we define a technique to separate the functionally distinct thymic NKT1, NKT2 and NKT17 cell subsets by their surface expression of CD278 (ICOS) and the activation‐associated glycoform of CD43, enabling the investigation of subset‐specific effector‐functions. We report that all three subsets express the transcription factor GATA‐3 and the potential to produce IL‐4 and IL‐10 following activation. This questions the notion that NKT2 cells are the predominant source of IL‐4 within the NKT cell pool, and suggests that IL‐10‐production may be more indicative of NKT cell plasticity than the existence of a distinct regulatory lineage or subset. We also show that many NKT17 cells are CD4+ and are biased toward Vβ8.3 TCR gene usage. Lastly, we demonstrate that the toll‐like receptor (TLR) ligand lipopolysaccharide (LPS) can induce a NKT17 cell‐biased response, even in the absence of exogenous antigen, and that combining LPS with α‐GalCer resulted in enhanced IL‐17A‐production, and reduced levels of the immunosuppressive cytokine IL‐10. This study provides a novel means to examine the context‐dependent reactivity of the functionally heterogeneous NKT cell population and provides important new insight into the functional biology of these subsets. Here, we define a technique to separate the functionally distinct NKT1, NKT2 and NKT17 cell subsets by their surface expression of ICOS and the activation‐associated glycoform of CD43, revealing that all three subsets produce IL‐4 and IL‐10 following activation. We also demonstrate that the toll‐like receptor ligand lipopolysaccharide (LPS) can induce a NKT17 cell‐biased response, even in the absence of exogenous antigen, and that combining LPS with α‐GalCer enhances IL‐17A‐production, while limiting production of IL‐10. This study provides a novel means to explore the context‐dependent reactivity of this functionally diverse population.

Key Points Whereas peptide–MHC complexes are the usual model for technology development focused on T cells, the discovery of lipids and non-lipid small molecules presented by CD1 and MHC class I-related protein (MR1) proteins expands the range of physiological antigens for human T cell responses. The human CD1 system consists of four antigen-presenting molecules, each with a different cell biological function. Most prior work on this system has focused on CD1d recognition by natural killer T (NKT) cells, but newly developed tetramers comprised of human CD1a, CD1b or CD1c molecules have created an opportunity to measure T cell function ex vivo in disease states. Many bacteria and fungi produce vitamin B metabolites (modified ribityl lumazines and ribityl pyrimidines), some of which can covalently bind in the A′ pocket of MR1 molecules and activate mucosal-associated invariant T (MAIT) cells. Whereas antigen-presenting cells trim large proteins into peptide antigens to fit the MHC groove, CD1 antigen processing starts with lipids that mostly match the CD1 cleft volume. Lipid antigens that are smaller than the cleft bind concomitantly with spacer lipids, and larger lipids are thought to protrude from the interior of CD1 proteins through accessory portals. Peptides span broadly across both sides of the MHC antigen display platform. Lipids bound to CD1 enter the T cell receptor (TCR) contact platform from the right side. This mode of binding creates a situation in which TCRs can predominantly contact CD1 protein or lipid, depending on whether the TCR takes a right-sided or left-sided approach. An unexpected mechanism for T cell autoreactivity was recently discovered in which a TCR binds directly to CD1a rather than to lipids carried in the cleft. Cellular CD1a proteins bind certain lipids with large head groups that disrupt the surface of CD1a. Such non-permissive ligands act by interfering with TCR contact to CD1a. NKT cells and MAIT cells are defined by TCRs that are nearly identical in all humans, and they bind CD1d and MR1 antigen-presenting molecules that are also nearly the same in all humans. New studies show that such invariant TCRs exist in the CD1b system and might be common in the human TCR repertoire. This Review focuses on the lesser studied antigen-presenting molecules group 1 CD1 proteins and MHC class I-related protein (MR1). The authors explain how their mode of presentation of lipids and small molecules to T cells differs from that of peptide–MHC presentation, and how new technologies are revealing unique T cell subsets that are specific for CD1 and MR1 proteins. The antigen-presenting molecules CD1 and MHC class I-related protein (MR1) display lipids and small molecules to T cells. The antigen display platforms in the four CD1 proteins are laterally asymmetrical, so that the T cell receptor (TCR)-binding surfaces are comprised of roofs and portals, rather than the long grooves seen in the MHC antigen-presenting molecules. TCRs can bind CD1 proteins with left-sided or right-sided footprints, creating unexpected modes of antigen recognition. The use of tetramers of human CD1a, CD1b, CD1c or MR1 proteins now allows detailed analysis of the human T cell repertoire, which has revealed new invariant TCRs that bind CD1b molecules and are different from those that define natural killer T cells and mucosal-associated invariant T cells.

NKT cells are a unique T lymphocyte sublineage that has been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, infectious diseases, and cancer. In stark contrast to both conventional T lymphocytes and other types of Tregs, NKT cells are reactive to the nonclassical class I antigen-presenting molecule CD1d, and they recognize glycolipid antigens rather than peptides. Moreover, they can either up- or downregulate immune responses by promoting the secretion of Th1, Th2, or immune regulatory cytokines. This review will explore the diverse influences of these cells in various disease models, their ability to suppress or enhance immunity, and the potential for manipulating these cells as a novel form of immunotherapy.

i NKT cells in adipose tissue are anti-inflammatory. Brenner and colleagues show that adipose i NKT cells have a unique transcriptional program, produce IL-2 and IL-10 and lack expression of the transcription factor PLZF. Invariant natural killer T cells ( i NKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. i NKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that i NKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other i NKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose i NKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (T reg cells) in adipose tissue. Thus, i NKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue.

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. This study uses MR1 tetramers to enumerate and phenotypically characterize human blood MAIT cells, and subsets thereof based on CD4 and CD8 expression. Furthermore MR1 tetramers are compared to the commonly used mAb‐based MAIT cell identification techniques.

Mucosal-associated invariant T (MAIT) cells express an invariant TRAV1/TRAJ33 TCR-α chain and are restricted to the MHC-I-like molecule, MR1. Whether MAIT cell development depends on this invariant TCR-α chain is unclear. Here we generate Traj33 -deficient mice and show that they are highly depleted of MAIT cells; however, a residual population remains and can respond to exogenous antigen in vitro or pulmonary Legionella challenge in vivo. These residual cells include some that express Trav1 + TCRs with conservative Traj -gene substitutions, and others that express Trav1 - TCRs with a broad range of Traj genes. We further report that human TRAV1-2 - MR1-restricted T cells contain both MAIT-like and non-MAIT-like cells, as judged by their TCR repertoire, antigen reactivity and phenotypic features. These include a MAIT-like population that expresses a public, canonical TRAV36 + TRBV28 + TCR. Our findings highlight the TCR diversity and the resulting potential impact on antigen recognition by MR1-restricted T cells. Mucosal-associated invariant T (MAIT) cells express invariant TRAV1/TRAJ33 TCR-α gene segments and detect antigens presented by MR1. Here the authors show that atypical, MR1-restricted MAIT populations that include both Trav1 + and Trav1- cells are found in both Traj33 -deficient mice and human peripheral blood.

Our understanding of the immune responses that follow SARS-CoV-2 infection and vaccination has progressed considerably since the COVID-19 pandemic was first declared on the 11 th of March in 2020. Recovery from infection is associated with the development of protective immune responses, although over time these become less effective against new emerging SARS-CoV-2 variants. Consequently, reinfection with SARS-CoV-2 variants is not infrequent and has contributed to the ongoing pandemic. COVID-19 vaccines have had a tremendous impact on reducing infection and particularly the number of deaths associated with SARS-CoV-2 infection. However, waning of vaccine induced immunity plus the emergence of new variants has necessitated the use of boosters to maintain the benefits of vaccination in reducing COVID-19 associated deaths. Boosting is also beneficial for individuals who have recovered from COVID-19 and developed natural immunity, also enhancing responses immune responses to SARS-CoV-2 variants. This review summarizes our understanding of the immune responses that follow SARS-CoV-2 infection and vaccination, the risks of reinfection with emerging variants and the very important protective role vaccine boosting plays in both vaccinated and previously infected individuals.

Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients. Newly diagnosed MM patient MAIT cells had reduced IFNγ production and CD27 expression, suggesting an exhausted phenotype, although IFNγ-producing capacity is restored in relapsed/refractory patient samples. Moreover, immunomodulatory drugs Lenalidomide and Pomalidomide, indirectly inhibited MAIT cell activation. We further show that cell lines can be pulsed with vitamin-B derivative Ags and that these can be presented via MR1 to MAIT cells in vitro , to induce cytotoxic activity comparable to that of natural killer (NK) cells. Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies.