Altered Distribution and Increased IL-17 Production by Mucosal-Associated Invariant T Cells in Adult and Childhood Obesity

Carolan, Eirin; Tobin, Laura; Mangan, Bozgana A.; Corrigan, Michelle; Gaoatswe, G.; Byrne, Greg; Geoghegan, Justin; Cody, Declan; O’Connell, Jean; Winter, Desmond C.; Doherty, Derek G.; Lynch, Lydia; O’Shea, Donal; Hogan, Andrew E.

doi:10.4049/jimmunol.1402945

Cited by 147 publications

(174 citation statements)

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“…This loss of peripheral blood MAIT cells in chronic HCV is in line with previous reports on other chronic infections such as untreated HIV-1 infection [29,30] and tuberculosis (TB) [31]. MAIT cells are also lost from the circulation during noninfectious chronic inflammatory conditions, including in patients with obesity and adipose tissue inflammation, and in systemic lupus erythematosus [32][33][34].To assess if the loss of MAIT cells was associated with changes in other immune cell subsets, we calculated pairwise correlations between all cellular subsets studied in the chronically infected HCV-patients (Fig. 1E).…”

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confidence: 74%

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction Mucosal-associated invariant T (MAIT) cells are T cells with innate-like characteristics enriched in human liver and at mucosalCorrespondence: Dr. Niklas K. Björkström e-mail: niklas.bjorkstrom@ki.se sites [1,2]. They express a semi-invariant TCR carrying the Vα7.2 segment together with a restricted Vβ repertoire [1,2]. Upon activation, MAIT cells respond rapidly with cellular cytotoxicity as well as secretion of proinflammatory and anti-viral cytokines such * These authors contributed equally to this work. HCV is an extremely successful pathogen in that it establishes chronic infection in up to 90% of infected humans [9]. The reasons behind the failure of the human immune system to clear HCV are not fully understood but involve viral escape, CD4 and CD8 T-cell exhaustion, as well as NK-cell dysfunction [10][11][12] Until recently, pegylated IFN-α together with ribavirin was used to treat chronic HCV-infection. However, pegylated IFN-α in doses administered to patients has direct inhibitory effects on immune cells [15][16][17][18]. In the last years, treatment of HCV has undergone a revolution with the introduction of highly effective direct-acting antivirals (DAA) that rapidly eliminate the virus [19]. Thus, today the vast majority of patients clear HCV after such IFN-free treatment regimens. This remarkable outcome allows for studies on consequences on immune cell recovery following rapid pathogen removal. In such studies, it was recently shown that both HCVspecific CD8 T cell and NK-cell populations become reinvigorated following viral clearance [20][21][22][23]. However, whether MAIT cells recover upon HCV clearance remains unclear.Here, we performed a comprehensive analysis of MAIT cells in chronic HCV-infection. Specifically, we addressed whether MAIT cell recovery occurs upon HCV-clearance in patients receiving an IFN-free treatment regimen consisting of sofosbuvir and ribavirin. Strikingly, and in contrast to other immune cells, MAIT cells were not reinvigorated following successful HCV-clearance using IFNfree therapy. The results are discussed in relation to the current knowledge on human MAIT cell responses to other viral infections and in the context of immune exhaustion during chronic infections. Results and discussion MAIT cells are among the most severely affected immune cells in chronic HCV-infectionTo determine the impact of chronic HCV-infection on the peripheral blood immune cell compartment, we assessed the major myeloid and lymphoid immune cell subsets in a cohort of HCVpatients and healthy donors by using a 23-parameter flow cytometry staining approach as previously described [24] (Supporting Information Fig. 1). The major phenotype observed in chronic HCV was a severe loss of MAIT cells (Fig. 1A, B). Other immune cell alterations noted were in line with previous studies, including an increase in Tregs [25], a reduced frequency of pDCs [26], and a shift within the CD4...

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confidence: 74%

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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“…Although obesity reduces circulating MAIT cell numbers at rest and high intensity and long duration exercise enhance lymphocytosis (Gleeson and Bishop 2005), we failed to observe any relationship with baseline MAIT cells or the change with acute exercise. Previously, severe obesity (BMI >45) was associated with low MAIT cells (Carolan et al 2015;Magalhaes et al 2015) whereas the current study had participants of normal body mass and % fat. Total GXT duration was relatively constant, which likely precluded our ability to observe a relationship.…”

Section: Discussionmentioning

confidence: 99%

“…Irritable bowel syndrome and Crohn's disease present with reduced frequency of systemic MAIT cells and higher IL-17 secretion whereas MAIT cell numbers within the intestinal mucosa show conflicting results (Hiejima et al 2015;Serriari et al 2014). Obesity and diabetes were also shown to reduce peripheral MAIT cell numbers with a subsequent increase within adipose tissue and higher IL-17 production (Carolan et al 2015;Magalhaes et al 2015). Individuals with severe asthma have been reported to have reduced MAIT cell counts in both the blood and lung tissue (Hinks et al 2015) with the magnitude of the decrement being correlated with clinical severity, indicating a potential relationship between MAIT cells and respiratory health.…”

Section: Introductionmentioning

confidence: 99%

“…A robust increase in MAIT cell with acute exercise in healthy individuals would provide a rationale to explore the use of exercise-induced lymphocytosis to enhance circulating MAIT cell counts during deficiencies. As obesity (Carolan et al 2015;Magalhaes et al 2015), fitness levels (Hong et al 2005), and exercise intensity and duration (Gleeson and Bishop 2005) influence circulating lymphocyte numbers, these factors need to be considered as possible mediators of the MAIT cell response to exercise.…”

Section: Introductionmentioning

confidence: 99%

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Maximal exercise increases mucosal associated invariant T cell frequency and number in healthy young men

et al. 2017

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Methods Twenty healthy young males with moderate fitness levels performed an extended graded exercise test until volitional fatigue. Peripheral blood mononuclear cells were isolated from venous blood obtained prior and immediately after exercise and were labeled to identify specific T cell populations using flow cytometry. Results The percentage of MAIT cells relative to total T cells significantly increased from 3.0 to 3.8% and absolute MAIT cell counts increased by 2.2-fold following maximal exercise. MAIT cell subpopulation proportions were unchanged with exercise. Within cytotoxic T lymphocytes (CTL), MAIT cells consisted of 8% of these cells and this remained constant after exercise. MAIT cell counts and changes with exercise were not affected by body composition, VO 2peak , or exercise duration. Conclusions Maximal exercise doubled MAIT cell numbers and showed preferential mobilization within total T cells but the response was not influenced by fitness levels, exercise duration, or body composition. These results suggest that acute exercise could be used to offset MAIT cell deficiencies observed with certain pathologies. MAIT cells also make up a substantial proportion of CTLs, which may have implications for cytotoxicity assays using these cells. Keywords TCR Vα7.2 · Exercise immunology · MAIT cells

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“…For example, adipose tissue is immunologically active and obesity causes a sterile inflammation80 in which iNKT may play an immunoregulatory role 81, 82. MAIT cells may contribute to this inflammation because in human obesity they are enriched in adipose tissue compared with blood, and have a shift towards higher IL‐17 production and reduced IL‐10 secretion 82, 83. In peripheral blood, MAIT cell frequencies are reduced in obesity and in type 2 diabetes, even below the limit of detection in some severely obese individuals,82 and display a more activated phenotype, with up‐regulated CD25 and IL‐17 production.…”

Section: Observations From Specific Diseasesmentioning

confidence: 99%

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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Altered Distribution and Increased IL-17 Production by Mucosal-Associated Invariant T Cells in Adult and Childhood Obesity

Cited by 147 publications

References 34 publications

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

Maximal exercise increases mucosal associated invariant T cell frequency and number in healthy young men

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

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