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Non-classical HLA restricted T cell subsets such as γδ T and NK-T cells are showing promises for immune-based therapy of hematological malignancies. Mucosal-Associated Invariant T cells (MAIT) belong to this family of innate-like T cell subsets and are the focus of many studies on infectious diseases, owing to their unusual recognition of bacterial/fungal metabolites. Their ability to produce type 1 cytokines (IFNγ, TNFα) as well as cytotoxic effector molecules endows them with potential anti-tumor functions. However, their contribution to tumor surveillance in solid cancers is unclear, and only few studies have specifically focused on MAIT cells in blood cancers. In this review, we wish to recapitulate our current knowledge on MAIT cells biology in hematological neoplasms, at diagnosis and/or during treatment, as well as tentative approaches to target them as therapeutic tools. We also wish to take this opportunity to briefly elaborate on what we think are important question to address in this field, as well as potential limitations to overcome in order to make MAIT cells the basis of future, novel therapies for hematological cancers.

A patient with severe idiopathic lymphopenia and progressive multifocal leukoencephalopathy had T-cell exhaustion and high expression of immune checkpoint markers. Treatment with the PD-1 blocker nivolumab led to a reduced CSF JC viral load, stable clinical features, and an immune reconstitution inflammatory response on MRI.

Allogenic graft acceptance is only achieved by life-long immunosuppression, which comes at the cost of significant toxicity. Clinicians face the challenge of adapting the patients’ treatments over long periods to lower the risks associated with these toxicities, permanently leveraging the risk of excessive versus insufficient immunosuppression. A major goal and challenge in the field of solid organ transplantation (SOT) is to attain a state of stable immune tolerance specifically towards the grafted organ. The immune system is equipped with a set of inhibitory co-receptors known as immune checkpoints (ICs), which physiologically regulate numerous effector functions. Insufficient regulation through these ICs can lead to autoimmunity and/or immune-mediated toxicity, while excessive expression of ICs induces stable hypo-responsiveness, especially in T cells, a state sometimes referred to as exhaustion. IC blockade has emerged in the last decade as a powerful therapeutic tool against cancer. The opposite action, i.e., subverting IC for the benefit of establishing a state of specific hypo-responsiveness against auto- or allo-antigens, is still in its infancy. In this review, we will summarize the available literature on the role of ICs in SOT and the relevance of ICs with graft acceptance. We will also discuss the possible influence of current immunosuppressive medications on IC functions.

Mucosal associated invariant T cells (MAIT) are innate T lymphocytes that detect a large variety of bacteria and yeasts. This recognition depends on the detection of microbial compounds presented by the evolutionarily conserved major-histocompatibility-complex (MHC) class I molecule, MR1. Here we show that MAIT cells display cytotoxic activity towards MR1 overexpressing non-hematopoietic cells cocultured with bacteria. The NK receptor, CD161, highly expressed by MAIT cells, modulated the cytokine but not the cytotoxic response triggered by bacteria infected cells. MAIT cells are also activated by and kill epithelial cells expressing endogenous levels of MRI after infection with the invasive bacteria Shigella flexneri. In contrast, MAIT cells were not activated by epithelial cells infected by Salmonella enterica Typhimurium. Finally, MAIT cells are activated in human volunteers receiving an attenuated strain of Shigella dysenteriae-1 tested as a potential vaccine. Thus, in humans, MAIT cells are the most abundant T cell subset able to detect and kill bacteria infected cells.

Mucosal-associated invariant T (MAIT) cells constitute a highly conserved subset of effector T cells with innate-like recognition of a wide array of bacteria and fungi in humans. Harnessing the potential of these cells could represent a major advance as a new immunotherapy approach to fight difficult-to-treat bacterial infections. However, despite recent advances in the design of potent agonistic ligands for MAIT cells, it has become increasingly evident that adjuvants are required to elicit potent antimicrobial effector functions by these cells, such as IFNγ production and cytotoxicity. Indeed, TCR triggering alone elicits mostly barrier repair functions in MAIT cells, whereas an inflammatory milieu is required to drive the antibacterial functions. Cytokines such as IL-7, IL-12 and IL-18, IL-15 or more recently type 1 IFN all display an apparently similar ability to synergize with TCR stimulation to induce IFNγ production and/or cytotoxic functions , but their mechanisms of action are not well established. Herein, we show that MAIT cells feature a build-in mechanism to respond to IFNα. We confirm that IFNα acts directly and specifically on MAIT cells and synergizes with TCR/CD3 triggering to induce maximum cytokine production and cytotoxic functions. We provide evidences suggesting that the preferential activation of the Stat4 pathway is involved in the high sensitivity of MAIT cells to IFNα stimulation. Finally, gene expression data confirm the specific responsiveness of MAIT cells to IFNα and pinpoints specific pathways that could be the target of this cytokine. Altogether, these data highlight the potential of IFNα-inducing adjuvants to maximize MAIT cells responsiveness to purified ligands in order to induce potent anti-infectious responses.

T cell exhaustion refers to a dysfunctional state in which effector T cells present a decreased ability to proliferate and to produce cytokines, while the co-expression of inhibitory receptors increases. We investigated global and donor-specific T cell responses in a cohort of stable, living-donor kidney transplant patients that received similar immunosuppression. After transplantation, an increase in the ratio of TIGIT + /CD226 + in mCD4 + T cells (r = 0.47, p = 0.01), and a decrease of CD226 + TIGIT-mCD4 + T cells was observed (r = − 0.55, p = 0.001). This leads to an increase of dysfunctional T cells in patients far from transplantation. In mCD8 + T cells, a decrease of IL-2 production after mitogenic stimulation was observed far from transplantation. Phenotypic analyses revealed an increase of mCD8 + T cells co-expressing PD-1 and TIGIT over time (r = 0.51, p = 0.02). After donor-specific stimulation, the ability of CD4 + T cells to proliferate was decreased compared with third parties. CD4 + T cells expressing CD226 and TIGIT were correlated with allospecific CD4 + proliferation (r = 0.68, p  = 0.04). Our study suggests that after kidney transplantation a T cell hyporesponsiveness appears over time, driven by a dysregulation of CD226/TIGIT axis in mCD4 + T cells, associated with an increase of PD1 + TIGIT + in mCD8 + T cells.

The evolutionary conservation of T lymphocyte subsets bearing T-cell receptors (TCRs) using invariant alpha-chains is indicative of unique functions. CD1d-restricted natural killer T (NK-T) cells that express an invariant Valpha14 TCRalpha chain have been implicated in microbial and tumour responses, as well as in auto-immunity. Here we show that T cells that express the canonical hValpha7.2-Jalpha33 or mValpha19-Jalpha33 TCR rearrangement are preferentially located in the gut lamina propria of humans and mice, respectively, and are therefore genuine mucosal-associated invariant T (MAIT) cells. Selection and/or expansion of this population requires B lymphocytes, as MAIT cells are absent in B-cell-deficient patients and mice. In addition, we show that MAIT cells are selected and/or restricted by MR1, a monomorphic major histocompatibility complex class I-related molecule that is markedly conserved in diverse mammalian species. MAIT cells are not present in germ-free mice, indicating that commensal flora is required for their expansion in the gut lamina propria. This indicates that MAIT cells are probably involved in the host response at the site of pathogen entry, and may regulate intestinal B-cell activity.

The pathophysiology of myelodysplastic syndromes (MDSs) is complex and often includes immune dysregulation of both the innate and adaptive immune systems. Whereas clonal selection mainly involves smoldering inflammation, a cellular immunity dysfunction leads to increased apoptosis and blast proliferation. Addressing immune dysregulations in MDS is a recent concept that has allowed the identification of new therapeutic targets. Several approaches targeting the different actors of the immune system have therefore been developed. However, the results are very heterogeneous, indicating the need to improve our understanding of the disease and interactions between chronic inflammation, adaptive dysfunction, and somatic mutations. This review highlights current knowledge of the role of immune dysregulation in MDS pathophysiology and the field of new drugs.

Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)alpha (iTCRalpha) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanValpha7.2 antibody and MAIT cell-specific iTCRalpha and TCRbeta transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRalpha and TCRbeta transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%-4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and gammadelta T cells.