Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

Gérart, Stéphane; Sibéril, Sophie; Martin, Emmanuel; Lenoir, Christelle; Aguilar, Claire; Pïcard, Capucine; Lantz, Olivier; Fischer, Alain; Latour, Sylvain

doi:10.1182/blood-2012-09-456095

Cited by 93 publications

(95 citation statements)

References 37 publications

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“…From the data presented here, it is clear that MAIT cell numbers in the lungs during LVS infection were not limited by the expansion and recruitment of classical MHC-restricted T cells, nor did MAIT cells lose functional capacity later in infection, as measured by their continued cytokine production. Interestingly, recent evidence indicates that the apoptotic propensity of human peripheral MAIT and iNKT cells is partially dependent on the balance between expression of proapoptotic proteins (including PLZF) and the antiapoptotic factor X-linked inhibitor of apoptosis (XIAP) (41). In light of the results presented in our murine model, it is possible that MAIT and iNKT cells possess different apoptotic sensitivities during infectious assaults.…”

Section: Discussionmentioning

confidence: 66%

MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection

Meierovics

Yankelevich

Cowley

2013

Proc. Natl. Acad. Sci. U.S.A.

312

358

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Mucosa-associated invariant T (MAIT) cells are "innate" T cells that express an invariant T-cell receptor α-chain restricted by the nonclassical MHC class I molecule MHC-related protein 1 (MR1). A recent discovery that MR1 presents vitamin B metabolites, presumably from pathogenic and/or commensal bacteria, distinguishes MAIT cells from peptide-or lipid-recognizing αβ T cells in the immune system. MAIT cells are activated by a wide variety of bacterial strains in vitro, but their role in defense against infectious assaults in vivo remains largely unknown. To investigate how MAIT cells contribute to mucosal immunity in vivo, we used a murine model of pulmonary infection by using the live vaccine strain (LVS) of Francisella tularensis. In the early acute phase of infection, MAIT cells expanded robustly in the lungs, where they preferentially accumulated after reaching their peak expansion in the late phase of infection. Throughout the course of infection, MAIT cells produced the critical cytokines IFN-γ, TNF-α, and IL-17A. Mechanistic studies showed that MAIT cells required both MR1 and IL-12 40 kDa subunit (IL-12p40) signals from infected antigen presenting cells to control F. tularensis LVS intracellular growth. Importantly, pulmonary F. tularensis LVS infection of MR1-deficient (MR1 −/− ) mice, which lack MAIT cells, revealed defects in early mucosal cytokine production, timely recruitment of IFN-γ-producing CD4 + and CD8 + T cells to the infected lungs, and control of pulmonary F. tularensis LVS growth. This study provides in vivo evidence demonstrating that MAIT cells are an important T-cell subset with activities that influence the innate and adaptive phases of mucosal immunity.tularemia | respiratory infection

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Section: Discussionmentioning

confidence: 66%

MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection

Meierovics

Yankelevich

Cowley

2013

Proc. Natl. Acad. Sci. U.S.A.

312

358

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“…Recent studies provided evidence that MAIT and NKT cells have a close lineage relationship and are highly susceptible to apoptosis, a feature not shared with conventional T cells (21,22,41). We next investigated the numerical and functional relationships between MAIT cells and NKT cells.…”

Section: Discussionmentioning

confidence: 99%

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

Cho

Kee

Kim

et al. 2014

The Journal of Immunology

146

159

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Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections and play an important role in mucosal immunity. However, the role of MAIT cells remains enigmatic in autoimmune diseases. In this study, we examined the level and function of MAIT cells in patients with rheumatic diseases. MAIT cell, cytokine, and programmed death-1 (PD-1) levels were measured by flow cytometry. Circulating MAIT cell levels were significantly reduced in systemic lupus erythematosus (SLE) and rheumatoid arthritis patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets, and significantly correlated with disease activity, such as SLE disease activity index and 28-joint disease activity score. Interestingly, MAIT cell frequency was significantly correlated with NKT cell frequency in SLE patients. IFN-γ production in MAIT cells was impaired in SLE patients, which was due to an intrinsic defect in the Ca2+/calcineurin/NFAT1 signaling pathway. In SLE patients, MAIT cells were poorly activated by α-galactosylceramide–stimulated NKT cells, thereby showing the dysfunction between MAIT cells and NKT cells. Notably, an elevated expression of PD-1 in MAIT cells and NKT cells was associated with SLE. In rheumatoid arthritis patients, MAIT cell levels were significantly higher in synovial fluid than in peripheral blood. Our study primarily demonstrates that MAIT cells are numerically and functionally deficient in SLE. In addition, we report a novel finding that this MAIT cell deficiency is associated with NKT cell deficiency and elevated PD-1 expression. These abnormalities possibly contribute to dysregulated mucosal immunity in SLE.

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“…Chronic haemorrhagic colitis is a common feature of X‐linked lymphoproliferative syndrome (XLP) type 2 20, 51. XLP‐2 is a rare human genetic immunodeficiency caused by mutations in the X‐linked inhibitor of apoptosis (XIAP) gene, leading to effects including increased apoptosis of iNKT and MAIT cells 20, 51.…”

Section: Observations From Specific Diseasesmentioning

confidence: 99%

“…XLP‐2 is a rare human genetic immunodeficiency caused by mutations in the X‐linked inhibitor of apoptosis (XIAP) gene, leading to effects including increased apoptosis of iNKT and MAIT cells 20, 51. XLP was therefore the first identified inherited immunodeficiency associated with iNKT or MAIT cell defects, with a 10‐fold decrease in peripheral blood MAIT cell frequencies 20. Colitis occurs in 17% of patients with XLP‐2 and resembles a severe form of inflammatory bowel disease, with accumulations of activated T cells and a mortality of 60% 51.…”

Section: Observations From Specific Diseasesmentioning

confidence: 99%

“…without the need for prior clonal expansion14 – typically CD45RA − CD45RO + CD95 Hi CD62L Lo CD44 Hi 2, 15, 16, 17 – and can rapidly secrete a range of pro‐inflammatory cytokines including tissue necrosis factor‐ α (TNF‐ α ), interleukin‐17 (IL‐17) and interferon‐ γ (IFN‐ γ ), and also the type 2 cytokine IL‐4 on TCR ligation 15, 17. MAIT cells share some similarities with invariant natural killer T (iNKT) cells, which are implicated in many autoimmune conditions,18, 19 including expression of a semi‐invariant TCR, restriction by non‐classical MHC molecules, and expression of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF)20 although many differences exist, notably the nature of the ligands and the restriction molecule. Other significant features are the remarkable abundance of MAIT cells, which comprise approximately 5% of T cells in peripheral blood11, 17 and 20–40% of liver T cells in humans,15, 21 and their wide tissue distribution in blood, mucosal tissues, liver and joints 15, 19, 22, 23, 24, 25.…”

Section: Introductionmentioning

confidence: 99%

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Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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SummaryMucosal‐associated invariant T (MAIT) cells are a novel class of innate‐like T cells, expressing a semi‐invariant T‐cell receptor (TCR) and able to recognize small molecules presented on the non‐polymorphic MHC‐related protein 1. Their intrinsic effector‐memory phenotype, enabling secretion of pro‐inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune‐mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation‐induced down‐regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR‐independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers.

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Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

Cited by 93 publications

References 37 publications

MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection

MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

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