The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity

Napier, Ruth J.; Adams, Erin J.; Gold, Marielle C.; Lewinsohn, David

doi:10.3389/fimmu.2015.00344

Cited by 107 publications

(91 citation statements)

References 52 publications

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“…Typhi (20), we hypothesized that changes in MAIT cell kinetics might be seen at even earlier time points (e.g., days 1 and 2) after the challenge. Innate-like T cells such as MAIT cells are known to respond very rapidly (<2 h) after activation and within the first few days postinfection (5, 21). To test this hypothesis, ex vivo PBMC collected before and up to 28 days after the challenge (including days 1 and 2) were surface stained with mAbs to CD3, CD4, CD8, CD14, CD19, CD161, and TCRα 7.2 and analyzed by multichromatic flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

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Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells

et al. 2017

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Gastrointestinal infections by Salmonella enterica serovar Typhi (S. Typhi) are rare in industrialized countries. However, they remain a major public health problem in the developing world with an estimated 26.9 million new cases annually and significant mortality when untreated. Recently, we provided the first direct evidence that CD8+ MAIT cells are activated and have the potential to kill cells exposed to S. Typhi, and that these responses are dependent on bacterial load. However, MAIT cell kinetics and function during bacterial infections in humans remain largely unknown. In this study, we characterize the human CD8+ MAIT cell immune response to S. Typhi infection in subjects participating in a challenge clinical trial who received a low- or high dose of wild-type S. Typhi. We define the kinetics of CD8+ MAIT cells as well as their levels of activation, proliferation, exhaustion/apoptosis, and homing potential. Regardless of the dose, in volunteers resistant to infection (NoTD), the levels of CD8+ MAIT cells after S. Typhi challenge fluctuated around their baseline values (day 0). In contrast, volunteers susceptible to the development of typhoid disease (TD) exhibited a sharp decline in circulating MAIT cells during the development of typhoid fever. Interestingly, MAIT cells from low-dose TD volunteers had higher levels of CD38 coexpressing CCR9, CCR6, and Ki67 during the development of typhoid fever than high-dose TD volunteers. No substantial perturbations on the levels of these markers were observed in NoTD volunteers irrespective of the dose. In sum, we describe, for the first time, that exposure to an enteric bacterium, in this case S. Typhi, results in changes in MAIT cell activation, proliferation, and homing characteristics, suggesting that MAIT cells are an important component of the human host response to bacterial infection.

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Section: Resultsmentioning

confidence: 99%

“…While thymic MAIT cells have the ability to respond to bacterial stimulation by upregulating activation (CD127) and proliferation (Ki67) markers, their cell surface phenotype is similar to that of naïve T cells (4, 5). After birth, MAIT cells acquire a memory phenotype and expand dramatically in the mucosa and periphery.…”

Section: Introductionmentioning

confidence: 99%

Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells

et al. 2017

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“…The existence of a high percentage of mycobacterial-reactive CD8 + T cells in uninfected healthy humans is also striking, as the stimulants for these CD8 + T cells must be shared between non-mycobacterial and mycobacterial organisms, and peptide antigens are least likely to explain this result. To date, we know MAIT cells respond to riboflavin precursor metabolites produced by a variety of bacterial species, including M. tuberculosis (21). Concurrently, MAIT cells have been shown to be protective against mycobacterial infection using infected mouse models deficient of MR1 protein or with overexpression of the MAIT cell TCR (20).…”

Section: Discoveries Of Unconventional T Cells In M Tuberculosis Infmentioning

confidence: 99%

Targeting Innate-Like T Cells in Tuberculosis

Huang

2016

Front. Immunol.

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Peptide-specific conventional T cells have been major targets for designing most antimycobacterial vaccines. Immune responses mediated by conventional T cells exhibit a delayed onset upon primary infection and are highly variable in different human populations. In contrast, innate-like T cells quickly respond to pathogens and display effector functions without undergoing extensive clonal expansion. Specifically, the activation of innate-like T cells depends on the promiscuous interaction of highly conserved antigen-presenting molecules, non-peptidic antigens, and likely semi-invariant T cell receptors. In antimicrobial immune responses, mucosal-associated invariant T cells are activated by riboflavin precursor metabolites presented by major histocompatibility complex-related protein I, while lipid-specific T cells including natural killer T cells are activated by lipid metabolites presented by CD1 proteins. Multiple innate-like T cell subsets have been shown to be protective or responsive in mycobacterial infections. Through rapid cytokine secretion, innate-like T cells function in early defense and memory response, offering novel advantages over conventional T cells in the design of anti-tuberculosis strategies.

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“…For example, the CD1 family (CD1a, CD1b, CD1c and CD1d) presents both foreign and self‐lipids to T cells that include the Natural Killer T cells and the germline‐encoded mycolyl lipid reactive T cells . Lastly, the MHC class‐I related molecule (MR1) presents small molecule metabolites to mucosal‐associated invariant T (MAIT) cells …”

Section: Introductionmentioning

confidence: 99%

Mucosal‐associated invariant T cell receptor recognition of small molecules presented by MR1

et al. 2018

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The major histocompatibility complex (MHC) class-I related molecule MR1 is a monomorphic and evolutionary conserved antigen (Ag)-presenting molecule that shares the overall architecture of MHC-I and CD1 proteins. However, in contrast to MHC-I and the CD1 family that present peptides and lipids, respectively, MR1 specifically presents small organic molecules. During microbial infection of mammalian cells, MR1 captures and presents vitamin B precursors, derived from the microbial biosynthesis of riboflavin, on the surface of antigen-presenting cells. These MR1-Ag complexes are recognized by the mucosal-associated invariant T cell receptor (MAIT TCR), which subsequently leads to MAIT cell activation. Recently, MR1 was shown to trap chemical scaffolds including drug and drug-like molecules. Here, we review this metabolite Ag-presenting molecule and further define the key molecular interactions underlying the recognition and reactivity of MAIT TCRs to MR1 in an Ag-dependent manner.

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The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity

Cited by 107 publications

References 52 publications

Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells

Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells

Targeting Innate-Like T Cells in Tuberculosis

Mucosal‐associated invariant T cell receptor recognition of small molecules presented by MR1

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