Primary Dendritic Cells Maturation of Monocyte-Derived and Invariant T Cells Induces CD40L-Dependent Activation of Human Mucosal-Associated

Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize intermediates of the vitamin B2 biosynthetic pathway presented by the monomorphic MR1 molecule. It remains unclear whether, in addition to their cytolytic activity that is important in antimicrobial defense, MAIT cells have immune-modulatory functions that could enhance dendritic cell (DC) maturation. In this study, we investigated the molecular mechanisms dictating the interactions between human MAIT cells and DCs and demonstrate that human MAIT cells mature monocyte-derived and primary DCs in an MR1- and CD40L-dependent manner. Furthermore, we show that MAIT cell–derived signals synergize with microbial stimuli to induce secretion of bioactive IL-12 by DCs. Activation of human MAIT cells in whole blood leads to MR1- and cytokine-dependent NK cell transactivation. Our results underscore an important property of MAIT cells, which can be of translational relevance to rapidly orchestrate adaptive immunity through DC maturation. The Journal of Immunology , 2017, 199: 000–000.

[1]  Joana Dias,et al.  Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines , 2017, Proceedings of the National Academy of Sciences.

[2]  A. Giobbie-Hurder,et al.  Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial , 2017, Clinical Cancer Research.

[3]  T. Ndung’u,et al.  The role of mucosal‐associated invariant T cells in infectious diseases , 2017, Immunology.

[4]  S. Cowley,et al.  MAIT cells promote inflammatory monocyte differentiation into dendritic cells during pulmonary intracellular infection , 2016, The Journal of experimental medicine.

[5]  I. Konstantinov,et al.  A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage , 2016, Nature Immunology.

[6]  J. McCluskey,et al.  The intracellular pathway for the presentation of vitamin B–related antigens by the antigen-presenting molecule MR1 , 2016, Nature Immunology.

[7]  G. Besra,et al.  Non‐glycosidic compounds can stimulate both human and mouse iNKT cells , 2016, European journal of immunology.

[8]  James McCluskey,et al.  Diversity of T Cells Restricted by the MHC Class I-Related Molecule MR1 Facilitates Differential Antigen Recognition. , 2016, Immunity.

[9]  J. McCluskey,et al.  The burgeoning family of unconventional T cells , 2015, Nature Immunology.

[10]  J. McCluskey,et al.  Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells* , 2015, The Journal of Biological Chemistry.

[11]  V. Cerundolo,et al.  Regulation of Lipid Specific and Vitamin Specific Non-MHC Restricted T Cells by Antigen Presenting Cells and Their Therapeutic Potentials , 2015, Front. Immunol..

[12]  J. McCluskey,et al.  MR1 presentation of vitamin B-based metabolite ligands. , 2015, Current opinion in immunology.

[13]  O. Lantz,et al.  In Vitro and In Vivo Analysis of the Gram-Negative Bacteria–Derived Riboflavin Precursor Derivatives Activating Mouse MAIT Cells , 2015, The Journal of Immunology.

[14]  V. Cerundolo,et al.  The Regulatory Role of Invariant NKT Cells in Tumor Immunity , 2015, Cancer Immunology Research.

[15]  P. Klenerman,et al.  MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets , 2014, Mucosal Immunology.

[16]  E. Newell,et al.  Correction: Corrigendum: Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire , 2014, Nature Communications.

[17]  D. Sinderen,et al.  T-cell activation by transitory neo-antigens derived from distinct microbial pathways , 2014, Nature.

[18]  James McCluskey,et al.  Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells , 2013, The Journal of experimental medicine.

[19]  P. Klenerman,et al.  CD161++CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner , 2013, European journal of immunology.

[20]  I. Hermans,et al.  Exploiting invariant NKT cells to promote T-cell responses to cancer vaccines , 2013, Oncoimmunology.

[21]  Malcolm J. McConville,et al.  MR1 presents microbial vitamin B metabolites to MAIT cells , 2012, Nature.

[22]  O. Lantz,et al.  Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. , 2011, Blood.

[23]  David M. Rissin,et al.  Single-Molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations , 2010, Nature Biotechnology.

[24]  D. Fremont,et al.  MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution , 2009, Proceedings of the National Academy of Sciences.

[25]  O. Lantz,et al.  Stepwise Development of MAIT Cells in Mouse and Human , 2009, PLoS biology.

[26]  D. Fremont,et al.  MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells , 2008, The Journal of experimental medicine.

[27]  Marion Pepper,et al.  Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. , 2007, Immunity.

[28]  D. Fremont,et al.  Evidence for MR1 Antigen Presentation to Mucosal-associated Invariant T Cells* , 2005, Journal of Biological Chemistry.

[29]  C. Sousa,et al.  Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function , 2005, Nature Immunology.

[30]  R. Steinman,et al.  The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation , 2004, The Journal of experimental medicine.

[31]  A. Harris,et al.  NKT Cells Enhance CD4+ and CD8+ T Cell Responses to Soluble Antigen In Vivo through Direct Interaction with Dendritic Cells 1 , 2003, The Journal of Immunology.

[32]  Olivier Lantz,et al.  Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1 , 2003, Nature.

[33]  D. Pellicci,et al.  Sequential production of interferon-gamma by NK1.1(+) T cells and natural killer cells is essential for the antimetastatic effect of alpha-galactosylceramide. , 2002, Blood.

[34]  A. Sher,et al.  CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. , 2000, Immunity.

[35]  A. Lanzavecchia.  Licence to kill , 1998 .

[36]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[37]  A. Lanzavecchia,et al.  Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation , 1996, The Journal of experimental medicine.

[38]  G. Maley,et al.  The isolation, synthesis, and metabolic properties of 6, 7-dimethyl-8-ribityllumazine. , 1959, The Journal of biological chemistry.

[39]  V. Cerundolo,et al.  Harnessing invariant NKT cells in vaccination strategies , 2009, Nature Reviews Immunology.

[40]  F. Oliveri,et al.  Myeloma based expression system for production of large mammalian proteins. , 1991, Trends in biotechnology.

[41]  D. D. Evans,et al.  976. The synthesis of 9-glycitylpurines, 3-glycityl-[1,2,3]-triazolo[d]-pyrimidines, 8-glycitylpteridines, and 10-glycitylbenzo[g]pteridines, including riboflavin and riboflavin 2-imine , 1960 .