Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites

Sakala, Isaac G., Kjer-Nielsen, Lars, Eickhoff, Christopher S., Wang, Xiaoli, Blazevic, Azra, Liu, Ligong, Fairlie, David P., Rossjohn, Jamie, McCluskey, James, Fremont, David H., Hansen, Ted H. and Hoft, Daniel F. (2015) Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites. The Journal of Immunology, 195 2: 587-601. doi:10.4049/jimmunol.1402545

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Author Sakala, Isaac G.
Kjer-Nielsen, Lars
Eickhoff, Christopher S.
Wang, Xiaoli
Blazevic, Azra
Liu, Ligong
Fairlie, David P.
Rossjohn, Jamie
McCluskey, James
Fremont, David H.
Hansen, Ted H.
Hoft, Daniel F.
Title Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites
Journal name The Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
1550-6606
Publication date 2015-06-10
Year available 2015
Sub-type Article (original research)
DOI 10.4049/jimmunol.1402545
Volume 195
Issue 2
Start page 587
End page 601
Total pages 15
Place of publication Bethesda, MD United States
Publisher American Association of Immunologists
Collection year 2016
Language eng
Formatted abstract
Mucosal-associated invariant T (MAIT) cells have a semi-invariant TCR Vα-chain, and their optimal development is dependent upon commensal flora and expression of the nonpolymorphic MHC class I–like molecule MR1. MAIT cells are activated in an MR1-restricted manner by diverse strains of bacteria and yeast, suggesting a widely shared Ag. Recently, human and mouse MR1 were found to bind bacterial riboflavin metabolites (ribityllumazine [RL] Ags) capable of activating MAIT cells. In this study, we used MR1/RL tetramers to study MR1 dependency, subset heterogeneity, and protective effector functions important for tuberculosis immunity. Although tetramer+ cells were detected in both MR1+/+ and MR1−/− TCR Vα19i-transgenic (Tg) mice, MR1 expression resulted in significantly increased tetramer+ cells coexpressing TCR Vβ6/8, NK1.1, CD44, and CD69 that displayed more robust in vitro responses to IL-12 plus IL-18 and RL Ag, indicating that MR1 is necessary for the optimal development of the classic murine MAIT cell memory/effector subset. In addition, tetramer+ MAIT cells expressing CD4, CD8, or neither developing in MR1+/+ Vα19i-Tg mice had disparate cytokine profiles in response to RL Ag. Therefore, murine MAIT cells are considerably more heterogeneous than previously thought. Most notably, after mycobacterial pulmonary infection, heterogeneous subsets of tetramer+ Vα19i-Tg MAIT cells expressing CXCR3 and α4β1 were recruited into the lungs and afforded early protection. In addition, Vα19iCα−/−MR+/+ mice were significantly better protected than were Vα19iCα−/−MR1−/−, wild-type, and MR1−/− non-Tg mice. Overall, we demonstrate considerable functional diversity of MAIT cell responses, as well as that MR1-restricted MAIT cells are important for tuberculosis protective immunity.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
 
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Created: Tue, 21 Jul 2015, 15:51:09 EST by Susan Allen on behalf of Institute for Molecular Bioscience