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

• Published in: Mucosal immunology Vol. 10; no. 1; pp. 58 - 68
• Main Authors: Chen, Z, Wang, H, D'Souza, C, Sun, S, Kostenko, L, Eckle, S B G, Meehan, B S, Jackson, D C, Strugnell, R A, Cao, H, Wang, N, Fairlie, D P, Liu, L, Godfrey, D I, Rossjohn, J, McCluskey, J, Corbett, A J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2017; Elsevier Limited
• Subjects: 631/250/2152/1566/1618; 631/250/255/1318; 631/250/347; 631/326/88; Allergology; Animals; Antibodies; Antigens, Bacterial - immunology; article-report; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Costimulatory and Inhibitory T-Cell Receptors - metabolism; Gastroenterology; Histocompatibility Antigens Class I - metabolism; Immunology; Interferon-gamma - metabolism; Interleukin-17 - metabolism; Lung - immunology; Lung - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Minor Histocompatibility Antigens - metabolism; Mucous Membrane - immunology; Natural Killer T-Cells - immunology; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Riboflavin - biosynthesis; Riboflavin - immunology; Salmonella Infections - immunology; Salmonella typhimurium - immunology; Signal Transduction; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - microbiology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2016.39

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.