IL-23 costimulates antigen-specific MAIT cell activation and enables vaccination against bacterial infection

2019 ◽  
Vol 4 (41) ◽  
pp. eaaw0402 ◽  
Author(s):  
Huimeng Wang ◽  
Lars Kjer-Nielsen ◽  
Mai Shi ◽  
Criselle D’Souza ◽  
Troi J. Pediongco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Activation ◽  
Cell Function ◽  
Dependent Manner ◽  
Mait Cells ◽  
Bone Marrow Derived Cells ◽  
Molecular Signals ◽  
Riboflavin Synthesis ◽  
Mait Cell

Mucosal-associated invariant T (MAIT) cells are activated in a TCR-dependent manner by antigens derived from the riboflavin synthesis pathway, including 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), bound to MHC-related protein-1 (MR1). However, MAIT cell activation in vivo has not been studied in detail. Here, we have found and characterized additional molecular signals required for optimal activation and expansion of MAIT cells after pulmonary Legionella or Salmonella infection in mice. We show that either bone marrow–derived APCs or non–bone marrow–derived cells can activate MAIT cells in vivo, depending on the pathogen. Optimal MAIT cell activation in vivo requires signaling through the inducible T cell costimulator (ICOS), which is highly expressed on MAIT cells. Subsequent expansion and maintenance of MAIT-17/1-type responses are dependent on IL-23. Vaccination with IL-23 plus 5-OP-RU augments MAIT cell–mediated control of pulmonary Legionella infection. These findings reveal cellular and molecular targets for manipulating MAIT cell function under physiological conditions.

scholarly journals Erratum: Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

Oncotarget ◽  
2015 ◽  
Vol 6 (38) ◽  
pp. 41398-41398 ◽  
Author(s):  
Han-Ching Tseng ◽  
Keiichi Kanayama ◽  
Kawaljit Kaur ◽  
So-Hyun Park ◽  
Sil Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Differential Modulation ◽  
Immune Cell Function

scholarly journals Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

Oncotarget ◽  
2015 ◽  
Vol 6 (24) ◽  
pp. 20002-20025 ◽  
Author(s):  
Han-Ching Tseng ◽  
Keiichi Kanayama ◽  
Kawaljit Kaur ◽  
So-Hyun Park ◽  
Sil Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Differential Modulation ◽  
Immune Cell Function

scholarly journals Influenza A Virus Infection v1

2020 ◽  
Author(s):  
Timothy S C Hinks ◽  
Bonnie van Wilgenburg ◽  
Huimeng Wang ◽  
Liyen Loh ◽  
Marios Koutsakos ◽  
...  
Keyword(s):  
Influenza A ◽  
Cell Activation ◽  
Viral Infections ◽  
Intracellular Cytokine Staining ◽  
Cell Receptor ◽  
Type I ◽  
Independent Manner ◽  
Mait Cells ◽  
Mait Cell

This is part 3.3 of the "Study of MAIT Cell Activation in Viral Infections In Vivo" collection of protocols. Collection Abstract: MAIT cells are abundant, highly evolutionarily conserved innate-like lymphocytes expressing a semi-invariant T cell receptor (TCR), which recognizes microbially derived small intermediate molecules from the riboflavin biosynthetic pathway. However, in addition to their TCR-mediated functions they can also be activated in a TCR-independent manner via cytokines including IL-12, -15, -18, and type I interferon. Emerging data suggest that they are expanded and activated by a range of viral infections, and significantly that they can contribute to a protective anti-viral response. Here we describe methods used to investigate these anti-viral functions in vivo in murine models. To overcome the technical challenge that MAIT cells are rare in specific pathogen-free laboratory mice, we describe how pulmonary MAIT cells can be expanded using intranasal bacterial infection or a combination of synthetic MAIT cell antigen and TLR agonists. We also describe protocols for adoptive transfer of MAIT cells, methods for lung homogenization for plaque assays, and surface and intracellular cytokine staining to determine MAIT cell activation.

scholarly journals MAIT cells are minimally responsive to Mycobacterium tuberculosis within granulomas, but are functionally impaired by SIV in a macaque model of SIV and Mtb co-infection

2020 ◽  
Author(s):  
Amy L. Ellis-Connell ◽  
Alexis J. Balgeman ◽  
Erica C. Larson ◽  
Mark A. Rodgers ◽  
Cassaundra Ameel ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cell Activation ◽  
Cell Function ◽  
Ex Vivo ◽  
Cynomolgus Macaque ◽  
Cross Sectional ◽  
In Vivo Models ◽  
Mait Cells ◽  
Mait Cell

ABSTRACTMucosal associated invariant T (MAIT) cells recognize and can directly destroy bacterially infected cells. While a role for MAIT cells has been suggested in several in vitro and in vivo models of M.tuberculosis (Mtb) infection, these studies have often focused on MAIT cells within the peripheral blood or are cross-sectional studies rather than longitudinal studies. The role of MAIT cells within granulomas and other sites of Mtb infection is relatively unknown. Furthermore, how HIV/SIV infection might impair MAIT cells at the sites of Mtb infection has not been determined. Using a Mauritian cynomolgus macaque (MCM) model system, we phenotyped MAIT cells in the peripheral blood and BAL prior to and during infection with SIVmac239. To characterize the role of MAIT cells within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb for 6 weeks. MAIT cell frequency and function was examined within the peripheral blood, distal airways, as well as within Mtb-affected lymph nodes (LN) and tissues. Surprisingly, we found no evidence of MAIT cell responsiveness to Mtb within granulomas. Additionally, MAIT cells only minimally responded to mycobacterial stimulus in ex vivo functional assays. In contrast, most MAIT cell activation seemed to occur in samples with highly active SIV replication, including blood and SIV-infected LN. Finally, the ability of MAIT cells to secrete TNFα (TNF) was impaired during SIV and Mtb co-infection, indicating that the two pathogens together could have a synergistically deleterious effect on MAIT cell function. The effect of this functional impairment on overall TB disease burden was unclear, but might be deleterious if MAIT cells are needed to fully activate antimycobacterial immune cells within the granulomas.

scholarly journals Legionella protection and vaccination mediated by Mucosal Associated Invariant T (MAIT) cells

2017 ◽  
Author(s):  
Huimeng Wang ◽  
Criselle D’Souza ◽  
Xin Yi Lim ◽  
Lyudmila Kostenko ◽  
Troi J Pediongco ◽  
...  
Keyword(s):  
Cell Activation ◽  
Cell Protection ◽  
Gm Csf ◽  
Mait Cells ◽  
Cell Immunity ◽  
Tnf Α ◽  
Ifn Γ ◽  
Clinically Significant ◽  
Riboflavin Synthesis ◽  
Mait Cell

AbstractMucosal associated invariant T (MAIT) cells recognize conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defense, yet their roles in protection against clinically significant pathogens are unknown. Murine Legionella infection induced MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in fully immunocompetent host animals. MAIT cell protection was more evident in mice lacking CD4+ cells, whilst profoundly immunodeficient RAG2−/−γC−/− mice were substantially rescued from uniformly lethal Legionella infection by adoptively-transferred MAIT cells. This protection was dependent on MR1, IFN-γ and GM-CSF, but not IL-17, TNF-α or perforin. Protection was enhanced and observed earlier post-infection in mice that were Ag-primed to boost MAIT cells before infection. Our findings define a significant role for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.

scholarly journals Outcome of SARS-CoV-2 infection linked to MAIT cell activation and cytotoxicity: evidence for an IL-18 dependent mechanism

2020 ◽  
Author(s):  
Héloïse Flament ◽  
Matthieu Rouland ◽  
Lucie Beaudoin ◽  
Amine Toubal ◽  
Léo Bertrand ◽  
...  
Keyword(s):  
Disease Severity ◽  
Cell Activation ◽  
Viral Infections ◽  
Immune Cell ◽  
Dependent Manner ◽  
Mait Cells ◽  
Inflammatory Phase ◽  
Immune System Dysfunction ◽  
Cell Counts ◽  
Mait Cell

Immune system dysfunction is paramount in Coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in a cohort of 182 patients including patients at various stages of disease activity. A profound decrease of MAIT cell counts in blood of critically ill patients was observed. These cells showed a strongly activated and cytotoxic phenotype that positively correlated with circulating pro-inflammatory cytokines, notably IL-18. MAIT cell alterations markedly correlated with disease severity and patient mortality. SARS-CoV-2-infected macrophages activated MAIT cells in a cytokine-dependent manner involving an IFNα-dependent early phase and an IL-18-induced later phase. Therefore, altered MAIT cell phenotypes represent valuable biomarkers of disease severity and their therapeutic manipulation might prevent the inflammatory phase involved in COVID-19 aggravation.

scholarly journals Activation of MAIT cells plays a critical role in viral vector vaccine immunogenicity

2019 ◽  
Author(s):  
Nicholas M. Provine ◽  
Ali Amini ◽  
Lucy C. Garner ◽  
Christina Dold ◽  
Claire Hutchings ◽  
...  
Keyword(s):  
Cell Activation ◽  
Viral Vector ◽  
Critical Role ◽  
Vector Vaccine ◽  
Future Design ◽  
Mait Cells ◽  
Lethal Infection ◽  
Mait Cell

AbstractMucosal-associated invariant T (MAIT) cells can be activated by viruses through a cytokine-dependent mechanism, and thereby protect from lethal infection. Given this, we reasoned MAIT cells may have a critical role in the immunogenicity of replication-incompetent adenovirus vectors, which are novel and highly potent vaccine platforms. In vitro, ChAdOx1 (Chimpanzee Adenovirus Ox1) induced potent activation of MAIT cells. Activation required transduction of monocytes and plasmacytoid dendritic cells to produce IL-18 and IFN-α, respectively. IFN-α-induced monocyte-derived TNF-α was identified as a novel intermediate in this activation pathway, and activation required combinatorial signaling of all three cytokines. Furthermore, ChAdOx1-induced in vivo MAIT cell activation in both mice and human volunteers. Strikingly, MAIT cell activation was necessary in vivo for development of ChAdOx1-induced HCV-specific CD8 T cell responses. These findings define a novel role for MAIT cells in the immunogenicity of viral vector vaccines, with potential implications for future design.One sentence summaryRobust immunogenicity of candidate adenovirus vaccine vectors requires the activation of unconventional T cells.

scholarly journals Lung Homogenization v1

2020 ◽  
Author(s):  
Timothy S C Hinks ◽  
Bonnie van Wilgenburg ◽  
Huimeng Wang ◽  
Liyen Loh ◽  
Marios Koutsakos ◽  
...  
Keyword(s):  
Cell Activation ◽  
Viral Infections ◽  
Intracellular Cytokine Staining ◽  
Cell Receptor ◽  
Type I ◽  
Independent Manner ◽  
Mait Cells ◽  
Specific Pathogen ◽  
Mait Cell

This is part 3.4 of the "Study of MAIT Cell Activation in Viral Infections In Vivo" collection of protocols. Collection Abstract: MAIT cells are abundant, highly evolutionarily conserved innate-like lymphocytes expressing a semi-invariant T cell receptor (TCR), which recognizes microbially derived small intermediate molecules from the riboflavin biosynthetic pathway. However, in addition to their TCR-mediated functions they can also be activated in a TCR-independent manner via cytokines including IL-12, -15, -18, and type I interferon. Emerging data suggest that they are expanded and activated by a range of viral infections, and significantly that they can contribute to a protective anti-viral response. Here we describe methods used to investigate these anti-viral functions in vivo in murine models. To overcome the technical challenge that MAIT cells are rare in specific pathogen-free laboratory mice, we describe how pulmonary MAIT cells can be expanded using intranasal bacterial infection or a combination of synthetic MAIT cell antigen and TLR agonists. We also describe protocols for adoptive transfer of MAIT cells, methods for lung homogenization for plaque assays, and surface and intracellular cytokine staining to determine MAIT cell activation.

scholarly journals MAIT Cell Adoptive Transfer v1

2020 ◽  
Author(s):  
Timothy S C Hinks ◽  
Bonnie van Wilgenburg ◽  
Huimeng Wang ◽  
Liyen Loh ◽  
Marios Koutsakos ◽  
...  
Keyword(s):  
Adoptive Transfer ◽  
Cell Activation ◽  
Viral Infections ◽  
Intracellular Cytokine Staining ◽  
Cell Receptor ◽  
Type I ◽  
Independent Manner ◽  
Mait Cells ◽  
Mait Cell

This is part 3.2 of the "Study of MAIT Cell Activation in Viral Infections In Vivo" collection of protocols. Collection Abstract: MAIT cells are abundant, highly evolutionarily conserved innate-like lymphocytes expressing a semi-invariant T cell receptor (TCR), which recognizes microbially derived small intermediate molecules from the riboflavin biosynthetic pathway. However, in addition to their TCR-mediated functions they can also be activated in a TCR-independent manner via cytokines including IL-12, -15, -18, and type I interferon. Emerging data suggest that they are expanded and activated by a range of viral infections, and significantly that they can contribute to a protective anti-viral response. Here we describe methods used to investigate these anti-viral functions in vivo in murine models. To overcome the technical challenge that MAIT cells are rare in specific pathogen-free laboratory mice, we describe how pulmonary MAIT cells can be expanded using intranasal bacterial infection or a combination of synthetic MAIT cell antigen and TLR agonists. We also describe protocols for adoptive transfer of MAIT cells, methods for lung homogenization for plaque assays, and surface and intracellular cytokine staining to determine MAIT cell activation.

scholarly journals Viral Plaque Assay v1

2020 ◽  
Author(s):  
Timothy S C Hinks ◽  
Bonnie van Wilgenburg ◽  
Huimeng Wang ◽  
Liyen Loh ◽  
Marios Koutsakos ◽  
...  
Keyword(s):  
Cell Activation ◽  
Viral Infections ◽  
Mdck Cells ◽  
Intracellular Cytokine Staining ◽  
Type I ◽  
Tissue Culture Dish ◽  
Mait Cells ◽  
Viral Plaque ◽  
Mait Cell

This is part 3.6 of the "Study of MAIT Cell Activation in Viral Infections In Vivo" collection of protocols. Collection Abstract: MAIT cells are abundant, highly evolutionarily conserved innate-like lymphocytes expressing a semi-invariant T cell receptor (TCR), which recognizes microbially derived small intermediate molecules from the riboflavin biosynthetic pathway. However, in addition to their TCR-mediated functions they can also be activated in a TCR-independent manner via cytokines including IL-12, -15, -18, and type I interferon. Emerging data suggest that they are expanded and activated by a range of viral infections, and significantly that they can contribute to a protective anti-viral response. Here we describe methods used to investigate these anti-viral functions in vivo in murine models. To overcome the technical challenge that MAIT cells are rare in specific pathogen-free laboratory mice, we describe how pulmonary MAIT cells can be expanded using intranasal bacterial infection or a combination of synthetic MAIT cell antigen and TLR agonists. We also describe protocols for adoptive transfer of MAIT cells, methods for lung homogenization for plaque assays, and surface and intracellular cytokine staining to determine MAIT cell activation. Abstract: Viral plaque assays are used to determine influenza viral titers. A diluted solution of egg-adapted Influenza A viruses/lung-infected tissue homogenates are applied to a six-well tissue culture dish containing a monolayer of Madin-Darby canine kidney (MDCK) cells. The infected MDCK cells grow under a semisolid overlay medium (agar) containing trypsin. A plaque is produced when a virus particle infects a cell, replicates, and then kills the cell. This process can be repeated several times as surrounding cells can be infected by newly replicated virus and killed. When visualized by eye, plaques appear as white spots. The assay is measured in PFU/mL.

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