Mucosal-associated invariant T cells are numerically and functionally deficient in patients with mycobacterial infection and reflect disease activity

Kwon, Yong Soo; Cho, Young-Nan; Kim, Moon‐Ju; Jin, Hye-Mi; Jung, Hyun‐Ju; Kang, Jeong-Hwa; Park, Ki-Jeong; Kim, Tae‐Jong; Kee, Hae Jin; Kim, Nacksung; Kee, Seung‐Jung; Park, Yong-Wook

doi:10.1016/j.tube.2015.03.004

Cited by 86 publications

(85 citation statements)

References 37 publications

(53 reference statements)

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“…1C, D). 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].…”

Section: Mait Cells Are Among the Most Severely Affected Immune Cellssupporting

confidence: 88%

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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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Section: Mait Cells Are Among the Most Severely Affected Immune Cellssupporting

confidence: 88%

“…2D). A similar profile of activated, and potentially exhausted, MAIT cells has been observed in chronic HIV-1 infection [29] and in patients with TB or systemic lupus erythematosus [31,33]. In HIV-1, the loss of MAIT cells may be partly due to downregulation of CD161 [29].…”

Section: Loss Of Mait Cells Is Nonreversible Despite Successful Ifn-fsupporting

confidence: 54%

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

et al. 2016

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“…Loss of MAIT cells has also been reported in cystic fibrosis (45), a genetic condition associated with chronic bacterial infections. Similarly, individuals carrying Helicobacter pylori, with mycobacterial infections, or patients with severe bacterial infection have lower blood MAIT cells (46)(47)(48). Overall, this suggests that the loss of MAIT cells in CVID and other diseases could reflect the infection burden.…”

Section: Discussionmentioning

confidence: 97%

Loss of Circulating Mucosal-Associated Invariant T Cells in Common Variable Immunodeficiency Is Associated with Immune Activation and Loss of Eomes and PLZF

et al. 2017

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Common variable immunodeficiency (CVID) is characterized by low levels of Igs leading to increased risk of infections. Mucosal-associated invariant T (MAIT) cells are a recently identified population of innate T cells with potent antibacterial activity. We hypothesized that CVID is associated with alterations in MAIT cells. Cryopreserved PBMC from CVID patients and healthy controls were used to study the frequency, phenotype, and response to Escherichia coli stimulation of MAIT cells by flow cytometry. MAIT cell frequency and absolute counts were depressed in CVID. Residual MAIT presented elevated coexpression of CD38 and HLA-DR, and reduced expression of CCR6, whereas levels of CD127 (IL-7 receptor) were unchanged. CVID patients also had an accumulation of MAIT cells lacking the critical transcription factors eomesodermin and promyelocytic leukemia zinc finger protein. MAIT cell frequency was inversely associated with levels of soluble CD14, with coexpression of CD38 and HLA-DR, and accumulation of MAIT cells lacking eomesodermin or promyelocytic leukemia zinc finger protein expression. None of these changes were normalized by IgG replacement therapy. Finally, MAIT cells from CVID patients displayed poor IFN-γ responses to E. coli stimulation, in part due to defective Ag presentation, and these responses were increased by pretreatment with IL-7. Defective MAIT cell response may contribute to the increased incidence of microbial infections seen in CVID patients on IgG replacement therapy.

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“…Other studies have confirmed that MAIT cell frequencies are decreased during active tuberculosis (and non-tuberculosis mycobacterial lung disease) in diverse geographic settings. 11,21,33,39 Peripheral depletion of MAIT cells is not, however, disease specific, with low levels of peripheral MAIT cells found in individuals with cystic fibrosis experiencing pulmonary exacerbations due to Pseudomonas aeruginosa, 40 non-streptococcal sepsis 41 and cholera. 42 There is evidence that the degree of peripheral MAIT depletion may correlate with disease severity and may be reversed with antibiotic treatment during recovery from illness.…”

Section: Insights From Study Of Human Cohortsmentioning

confidence: 99%

“…42 There is evidence that the degree of peripheral MAIT depletion may correlate with disease severity and may be reversed with antibiotic treatment during recovery from illness. 11,[39][40][41] Interestingly, in a study of peripheral MAIT cells in intensive care unit patients with sepsis, failure of peripheral MAIT cells to rise during the intensive care unit stay was correlated with the subsequent acquisition of secondary infections. 41 Depletion of MAIT cells in the peripheral blood is not specific to bacterial infection and is also observed in …”

Section: Insights From Study Of Human Cohortsmentioning

confidence: 99%

The role of mucosal‐associated invariant T cells in infectious diseases

2016

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SummaryMucosal-associated invariant T (MAIT) cells are donor-unrestricted lymphocytes that are surprisingly abundant in humans, representing 1-10% of circulating T cells and further enriched in mucosal tissues. MAIT cells recognize and are activated by small molecule ligands produced by microbes and presented by MR1, a highly conserved MHC-related antigen-presenting protein that is ubiquitously expressed in human cells. Increasing evidence suggests that MAIT cells play a protective role in anti-bacterial immunity at mucosal interfaces. Some fungi are known to produce MAIT-activating ligands, but the role of MAIT cells in fungal infections has not yet been investigated. In viral infections, specifically HIV, which has received the most study, MAIT cell biology is clearly altered, but the mechanisms explaining these alterations and their clinical significance are not yet understood. Many questions remain unanswered about the potential of MAIT cells for protection or pathogenesis in infectious diseases. Because they interact with the universal, donor-unrestricted ligand-presenting MR1 molecule, MAIT cells may be attractive immunotherapy or vaccine targets. New tools, including the development of MR1-ligand tetramers and next-generation T-cell receptor sequencing, have the potential to accelerate MAIT cell research and lead to new insights into the role of this unique set of lymphocytes in infectious diseases.

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Mucosal-associated invariant T cells are numerically and functionally deficient in patients with mycobacterial infection and reflect disease activity

Cited by 86 publications

References 37 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

Loss of Circulating Mucosal-Associated Invariant T Cells in Common Variable Immunodeficiency Is Associated with Immune Activation and Loss of Eomes and PLZF

The role of mucosal‐associated invariant T cells in infectious diseases

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