Mucosal-associated invariant T cells in hematological malignancies: Current knowledge, pending questions

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

Stepwise Development of MAIT Cells in Mouse and Human

Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)α (iTCRα) 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-humanVα7.2 antibody and MAIT cell-specific iTCRα and TCRβ 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 iTCRα and TCRβ 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 γδ T cells

Caractérisation de la sous-population lymphocytaire MAIT au cours des maladies inflammatoires chroniques de l'intestin

Introduction: La réaction immunitaire intestinale dans les MICI serait une réaction envers la flore endogène et serait sous l influence de facteurs génétiques. Les cellules MAIT sont une sous-population lymphocytaire T mémoire effectrice, CD8+ ou CD4-CD8-, activées par la flore endogène et caractérisées par un tropisme tissulaire intestinal important. Nous avons étudié le comportement ex-vivo de ces cellules extraites de la circulation sanguine périphérique au cours des MICI. Méthodes: 40 patients atteints de MICI (31 MC et 9 RCH) et 44 témoins ont été inclus dans cette étude prospective. Le taux de cellules MAIT circulantes et l expression de CCR6, NKG2D, BTLA, IL23R et Ki67 par ces cellules ont été étudiés. Les productions de cytokines de type Th1, Th2, Th17 et d IL10 après stimulation par une association PMA + Ionomycine ont été recherchées. Résultats: Il existe une diminution significative du taux de cellules MAIT/CD8+ circulantes dans les MICI (p < 0.0001). L expression de CCR6 est significativement augmentée à la surface des MAIT/CD8+ dans la MC. Les expressions de BTLA et NKG2D sont significativement augmentées dans les MICI (p < 0.0001). Ces cellules sont plus prolifératives avec un taux d expression de Ki67 augmenté dans la MC (p = 0.0022). Les MAIT produisent significativement plus d IL17 dans les MICI et moins d IFN dans la MC. Conclusion: Les cellules MAIT sont activées dans les MICI, présentent un probable tropisme intestinal exacerbé et produisent des cytokines pro-inflammatoires Th1-Th17. Leur intervention dans le mécanisme physiopathologique de ces maladies est donc probable.Background: The pathophysiology of Inflammatory Bowel Disease (IBD) is still unknown. Microbiota disorders as well as genetic factors may underlie the inflammatory immune response in IBD. MAIT cells are a subset of effector/memory CD8+/CD4-CD8- T cells, highly conserved in evolution. They are abundant in the liver and intestinal mucosa, and may be activated by the endogenous flora. We performed an ex-vivo study of these cells in the peripheral blood of patients with IBD. Methods: 40 patients were included (Crohn disease (CD) n=31, Ulcerative Colitis (UC) n=9) in this study. The proportion of peripheral blood MAIT cells and their expression of several markers such as CCR6, NKG2D, BTLA, IL23R and Ki67 were analyzed. We also assessed their pattern of cytokine secretion after in vitro stimulation with PMA and ionomycine. Results: The frequency of CD8+ MAIT cells is significantly decreased in the peripheral blood of IBD patients (p < 0.0001). CCR6 expression by CD8+ MAIT cells is significantly increased in CD. BTLA and NKG2D expression by MAIT cells is significantly increased in IBD (p < 0.0001). MAIT cells were more proliferative in IBD with Ki67 expression highly increased (p = 0.0022). After in vitro simulation, MAIT cells produced significantly more IL-17, both in CD and UC and less IFN only in CD. Conclusion: Diminution of MAIT cells in the peripheral blood of IBD patients may be secondary to a more important intestinal tropism, as suggested by the increased expression of CCR6. MAIT cells produce Th1-Th17 pro-inflammatory cytokine; have an unusually proliferative profile, an increased expression of the costimulatory NKG2D and of the inhibitory BTLA molecules. Altogether, MAIT cells may be implicated in the pathophysiology of IBD.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Les cellules M.A.I.T(Mucosal associated invariant T):une nouvelle sous population phylogénétiquement conservée de lymphocytes T à répertoire invariant.

PARIS-BIUP (751062107) / SudocSudocFranceF

DEVELOPPEMENT, PHENOTYPE ET LOCALISATION TISSULAIRE DES LYMPHOCYTES T EXPRIMANT LA CHAINE INVARIANTE DU TCR V ALPHA 7.2/19-J ALPHA33 (DES BIOL. MED.)

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

T cell reconstitution after lymphocyte depletion features a different pattern of inhibitory receptor expression in ABO‐ versus HLA‐incompatible kidney transplant recipients

International audienceChronic antigen stimulation can lead to immune exhaustion (a state of T cell dysfunction). Several phenotypical signatures of T cell exhaustion have been described in various pathological situations, characterized by aberrant expression of multiple inhibitory receptors (IR). This signature has been barely studied in the context of allogenic organ transplantation. We undertook a cross‐sectional analysis of the expression of IR [CD244, CD279, T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine‐based inhibition motif (ITIM) domains (TIGIT) and CD57] and their correlation with cytokine‐producing functions in T cells reconstituting after lymphocyte depletion in patients transplanted from living donors, with preformed donor‐specific antibodies. After ABO incompatible transplantation, T cells progressively acquired a phenotype similar to healthy donors and the expression of several IR marked cells with increased functions, with the exception of TIGIT, which was associated with decreased cytokine production. In stark contrast, T cell reconstitution in patients with anti‐human leukocyte antigen (HLA) antibodies was characterized with an increased co‐expression of IR by T cells, and specifically by an increased expression of TIGIT. Furthermore, expression of these receptors was no longer directly correlated to cytokine production. These results suggest that T cell alloreactivity in HLA‐incompatible kidney transplantation drives an aberrant T cell reconstitution with respect to IR profile, which could have an impact on the transplantation outcome

MAIT Cells Display a Specific Response to Type 1 IFN Underlying the Adjuvant Effect of TLR7/8 Ligands

International audienceMucosal-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 in vitro, 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

NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model.

International audienceInhibitory receptors that engage self-MHC class I molecules enable NK cells to detect disease-associated loss of MHC class I on surrounding cells. Previous studies showed that some NK cells lack all receptors for self-MHC class I, yet fail to exhibit autoimmunity because they are generally hyporesponsive to stimulation. We asked whether NK cells exist in only two states, responsive and hyporesponsive, corresponding to cells that express or fail to express inhibitory receptors for self-MHC class I. The alternative model is that NK cells vary continuously in their responsiveness, based on variations in the number of different inhibitory and stimulatory receptors they express, which is known to vary. In this study, we show in the murine system that NK cell responsiveness increases quantitatively with each added self-MHC-specific inhibitory receptor. Genetic analysis demonstrated that interactions of each of the receptors with self-MHC class I were necessary to observe augmented responsiveness. These findings suggest that NK cell responsiveness is comparable to a rheostat: it is tuned to an optimal set point depending on the inhibitory and stimulatory interactions encountered in the normal environment, so as to ensure self-tolerance and yet optimize sensitivity to changes in normal cells

Novel T cell interferon gamma release assay (IGRA) using spike recombinant protein for COVID19 vaccine response and Nucleocapsid for SARS-Cov2 response

International audienc