Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals

Z Chen, H Wang, C D'Souza, S Sun, L Kostenko, SBG Eckle, BS Meehan, DC Jackson, RA Strugnell, H Cao, N Wang, DP Fairlie, L Liu, DI Godfrey, J Rossjohn, J McCluskey, AJ Corbett

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Abstract

Despite recent breakthroughs in identifying mucosal-associated invariant T (MAIT) cell antigens (Ags), the precise requirements for in vivo MAIT cell responses to infection remain unclear. Using major histocompatibility complex–related protein 1 (MR1) tetramers, the MAIT cell response was investigated in a model of bacterial lung infection employing riboflavin gene-competent and -deficient bacteria. MAIT cells were rapidly enriched in the lungs of C57BL/6 mice infected with Salmonella Typhimurium, comprising up to 50% of αβ-T cells after 1 week. MAIT cell accumulation was MR1-dependent, required Ag derived from the microbial riboflavin synthesis pathway, and did not occur in response to synthetic Ag, unless accompanied by a Toll-like receptor agonist or by co-infection with riboflavin pathway-deficient S. Typhimurium. The MAIT cell response was associated with their long-term accumulation in the lungs, draining lymph nodes and spleen. Lung MAIT cells from infected mice displayed an activated/memory phenotype, and most expressed the transcription factor retinoic acid–related orphan receptor γt. T-bet expression increased following infection. The majority produced interleukin-17 while smaller subsets produced interferon-γ or tumor necrosis factor, detected directly ex vivo. Thus the activation and expansion of MAIT cells coupled with their pro-inflammatory cytokine production occurred in response to Ags derived from microbial riboflavin synthesis and was augmented by co-stimulatory signals.
Original languageEnglish
Pages (from-to)58-68
Number of pages11
JournalMucosal Immunology
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Cite this

Chen, Z ; Wang, H ; D'Souza, C ; Sun, S ; Kostenko, L ; Eckle, SBG ; Meehan, BS ; Jackson, DC ; Strugnell, RA ; Cao, H ; Wang, N ; Fairlie, DP ; Liu, L ; Godfrey, DI ; Rossjohn, J ; McCluskey, J ; Corbett, AJ. / Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. In: Mucosal Immunology. 2017 ; Vol. 10, No. 1. pp. 58-68.
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title = "Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals",
abstract = "Despite recent breakthroughs in identifying mucosal-associated invariant T (MAIT) cell antigens (Ags), the precise requirements for in vivo MAIT cell responses to infection remain unclear. Using major histocompatibility complex–related protein 1 (MR1) tetramers, the MAIT cell response was investigated in a model of bacterial lung infection employing riboflavin gene-competent and -deficient bacteria. MAIT cells were rapidly enriched in the lungs of C57BL/6 mice infected with Salmonella Typhimurium, comprising up to 50{\%} of αβ-T cells after 1 week. MAIT cell accumulation was MR1-dependent, required Ag derived from the microbial riboflavin synthesis pathway, and did not occur in response to synthetic Ag, unless accompanied by a Toll-like receptor agonist or by co-infection with riboflavin pathway-deficient S. Typhimurium. The MAIT cell response was associated with their long-term accumulation in the lungs, draining lymph nodes and spleen. Lung MAIT cells from infected mice displayed an activated/memory phenotype, and most expressed the transcription factor retinoic acid–related orphan receptor γt. T-bet expression increased following infection. The majority produced interleukin-17 while smaller subsets produced interferon-γ or tumor necrosis factor, detected directly ex vivo. Thus the activation and expansion of MAIT cells coupled with their pro-inflammatory cytokine production occurred in response to Ags derived from microbial riboflavin synthesis and was augmented by co-stimulatory signals.",
author = "Z Chen and H Wang and C D'Souza and S Sun and L Kostenko and SBG Eckle and BS Meehan and DC Jackson and RA Strugnell and H Cao and N Wang and DP Fairlie and L Liu and DI Godfrey and J Rossjohn and J McCluskey and AJ Corbett",
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Chen, Z, Wang, H, D'Souza, C, Sun, S, Kostenko, L, Eckle, SBG, Meehan, BS, Jackson, DC, Strugnell, RA, Cao, H, Wang, N, Fairlie, DP, Liu, L, Godfrey, DI, Rossjohn, J, McCluskey, J & Corbett, AJ 2017, 'Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals', Mucosal Immunology, vol. 10, no. 1, pp. 58-68. https://doi.org/10.1038/mi.2016.39

Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. / Chen, Z; Wang, H; D'Souza, C; Sun, S; Kostenko, L; Eckle, SBG; Meehan, BS; Jackson, DC; Strugnell, RA; Cao, H; Wang, N; Fairlie, DP; Liu, L; Godfrey, DI; Rossjohn, J; McCluskey, J; Corbett, AJ.

In: Mucosal Immunology, Vol. 10, No. 1, 01.01.2017, p. 58-68.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals

AU - Chen, Z

AU - Wang, H

AU - D'Souza, C

AU - Sun, S

AU - Kostenko, L

AU - Eckle, SBG

AU - Meehan, BS

AU - Jackson, DC

AU - Strugnell, RA

AU - Cao, H

AU - Wang, N

AU - Fairlie, DP

AU - Liu, L

AU - Godfrey, DI

AU - Rossjohn, J

AU - McCluskey, J

AU - Corbett, AJ

PY - 2017/1/1

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