Lung epithelial signaling mediates early vaccine-induced CD4+ T cell activation and Mtb control

Tuberculosis (TB) is one of the leading causes of death due to a single infectious agent. The development of a TB vaccine that induces durable and effective immunity to Mycobacterium tuberculosis (Mtb) infection is urgently needed. Early and superior Mtb control can be induced in M. bovis Bacillus Calmette–Guérin (BCG) vaccinated hosts when the innate immune response is targeted to generate effective vaccine-induced immunity. In the present study, we show that innate activation of DCs is critical for mucosal localization of clonally activated vaccine-induced CD4+ T cells in the lung, and superior early Mtb control. In addition, our study reveals that Th1/Th17 cytokine axis play an important role in superior vaccine induced immunity. Our studies also show that activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκβ) pathway in lung epithelial cells is critical for the mucosal localization of activated vaccine-induced CD4+ T cells for rapid Mtb control. Thus, our study provides novel insights into the immune mechanisms that can overcome TB vaccine bottlenecks and provide early rapid Mtb control. Importance Tuberculosis is a leading cause of death due to single infectious agent accounting 1.4 million deaths each year. The only licensed vaccine BCG is not effective due to variable efficacy. In our study, we determined the early immune events necessary for achieving complete protection in BCG vaccinated host. Our study reveals that innate activation of DCs can mediate superior and early Mtb control in BCG vaccinated host through lung epithelial cell signaling and localization of clonal activated, Mtb antigen specific, cytokine producing CD4+ T cells within the lung parenchyma and airways. Thus, our study provides novel insights into the immune mechanisms that can overcome TB vaccine bottlenecks and provide early rapid Mtb control.

[1]  J. Rengarajan,et al.  Pulmonary Mycobacterium tuberculosis control associates with CXCR3- and CCR6-expressing antigen-specific Th1 and Th17 cell recruitment. , 2020, JCI insight.

[2]  T. Scriba,et al.  Tuberculosis Vaccine Development: Progress in Clinical Evaluation , 2019, Clinical Microbiology Reviews.

[3]  M. Demoitié,et al.  Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis. , 2019, The New England journal of medicine.

[4]  Jing Wang,et al.  WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs , 2019, Nucleic Acids Res..

[5]  T. Ndung’u,et al.  Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis , 2019, Nature.

[6]  A. Leslie,et al.  Lung Tissue Resident Memory T-Cells in the Immune Response to Mycobacterium tuberculosis , 2019, Front. Immunol..

[7]  A. McDermott,et al.  Lung Epithelial Cells Coordinate Innate Lymphocytes and Immunity against Pulmonary Fungal Infection. , 2019, Cell host & microbe.

[8]  T. Ottenhoff,et al.  Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques , 2019, Nature Medicine.

[9]  Minoru Kanehisa,et al.  New approach for understanding genome variations in KEGG , 2018, Nucleic Acids Res..

[10]  M. Mitreva,et al.  A novel role for C-C motif chemokine receptor 2 during infection with hypervirulent Mycobacterium tuberculosis , 2018, Mucosal Immunology.

[11]  Paul Hoffman,et al.  Integrating single-cell transcriptomic data across different conditions, technologies, and species , 2018, Nature Biotechnology.

[12]  Mahavir Singh,et al.  Mucosal Delivery of Fusion Proteins with Bacillus subtilis Spores Enhances Protection against Tuberculosis by Bacillus Calmette-Guérin , 2018, Front. Immunol..

[13]  E. Agger,et al.  T Cells Primed by Live Mycobacteria Versus a Tuberculosis Subunit Vaccine Exhibit Distinct Functional Properties , 2017, EBioMedicine.

[14]  S. Behar,et al.  Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis , 2017, PLoS pathogens.

[15]  Yufeng Shen,et al.  Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. , 2017, Cell reports.

[16]  P. Bradley,et al.  Quantifiable predictive features define epitope-specific T cell receptor repertoires , 2017, Nature.

[17]  Courtney R. Plumlee,et al.  Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis. , 2017, Cell host & microbe.

[18]  A. Thomas,et al.  Variable BCG efficacy in rhesus populations: Pulmonary BCG provides protection where standard intra-dermal vaccination fails. , 2017, Tuberculosis.

[19]  D. Barber,et al.  Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis. , 2017, Cell reports.

[20]  J. Alcorn,et al.  Novel role for IL-22 in protection during chronic Mycobacterium tuberculosis HN878 infection , 2017, Mucosal Immunology.

[21]  Y. Gilad,et al.  Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells , 2017, bioRxiv.

[22]  G. Lal,et al.  Role of chemokine receptors and intestinal epithelial cells in the mucosal inflammation and tolerance , 2017, Journal of leukocyte biology.

[23]  Maxim N. Artyomov,et al.  Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy , 2016, Nature Communications.

[24]  W. Jacobs,et al.  Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation , 2016, Nature Microbiology.

[25]  Ajay S. Gulati,et al.  Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation. , 2016, Immunity.

[26]  Guang-Biao Zhou,et al.  The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution , 2015, eLife.

[27]  A. Lackner,et al.  Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis , 2015, Nature Communications.

[28]  J. Kolls,et al.  Unexpected Role for IL-17 in Protective Immunity against Hypervirulent Mycobacterium tuberculosis HN878 Infection , 2014, PLoS pathogens.

[29]  D. Barber,et al.  Cutting Edge: Control of Mycobacterium tuberculosis Infection by a Subset of Lung Parenchyma–Homing CD4 T Cells , 2014, The Journal of Immunology.

[30]  M. Selman,et al.  S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. , 2013, American journal of respiratory and critical care medicine.

[31]  M. Pasparakis,et al.  Selective Ablation of Lung Epithelial IKK2 Impairs Pulmonary Th17 Responses and Delays the Clearance of Pneumocystis , 2013, The Journal of Immunology.

[32]  J. Ernst,et al.  Cutting Edge: Direct Recognition of Infected Cells by CD4 T Cells Is Required for Control of Intracellular Mycobacterium tuberculosis In Vivo , 2013, The Journal of Immunology.

[33]  P. Saha,et al.  Recruitment of Th1 effector cells in human tuberculosis: hierarchy of chemokine receptor(s) and their ligands. , 2013, Cytokine.

[34]  S. Vigano,et al.  Lack of Mycobacterium tuberculosis–specific interleukin‐17A–producing CD4+ T cells in active disease , 2013, European journal of immunology.

[35]  M. Selman,et al.  CXCR5⁺ T helper cells mediate protective immunity against tuberculosis. , 2013, The Journal of clinical investigation.

[36]  Bjoern Peters,et al.  Memory T Cells in Latent Mycobacterium tuberculosis Infection Are Directed against Three Antigenic Islands and Largely Contained in a CXCR3+CCR6+ Th1 Subset , 2013, PLoS pathogens.

[37]  T. Blackwell,et al.  Cooperation between classical and alternative NF-κB pathways regulates proinflammatory responses in epithelial cells. , 2012, American journal of respiratory cell and molecular biology.

[38]  A. Verkman,et al.  Chemokine-dependent T cell migration requires aquaporin-3–mediated hydrogen peroxide uptake , 2012, The Journal of experimental medicine.

[39]  R. Gopal,et al.  IL‐23‐dependent IL‐17 drives Th1‐cell responses following Mycobacterium bovis BCG vaccination , 2012, European journal of immunology.

[40]  J. Ernst,et al.  Initiation and regulation of T-cell responses in tuberculosis , 2011, Mucosal Immunology.

[41]  S. Connolly,et al.  Small molecule antagonists of CCR8 inhibit eosinophil and T cell migration. , 2011, Biochemical and biophysical research communications.

[42]  J. Kolls,et al.  IL-23 Is Required for Long-Term Control of Mycobacterium tuberculosis and B Cell Follicle Formation in the Infected Lung , 2011, The Journal of Immunology.

[43]  C. Harding,et al.  Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors , 2010, Nature Reviews Microbiology.

[44]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[45]  A. Mcdonald,et al.  CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3+ Regulatory and Th2 Effector Lymphocytes , 2006, The Journal of Immunology.

[46]  J. Kolls,et al.  Role of IL-17A, IL-17F, and the IL-17 Receptor in Regulating Growth-Related Oncogene-α and Granulocyte Colony-Stimulating Factor in Bronchial Epithelium: Implications for Airway Inflammation in Cystic Fibrosis 1 , 2005, The Journal of Immunology.

[47]  Eric C. Lai,et al.  Notch signaling: control of cell communication and cell fate , 2004, Development.

[48]  P. Sopp,et al.  Dendritic Cells Induce CD4+ and CD8+ T‐Cell Responses to Mycobacterium bovis and M. avium Antigens in Bacille Calmette Guérin Vaccinated and Nonvaccinated Cattle , 2000, Scandinavian journal of immunology.

[49]  D. Beier,et al.  Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. , 1999, Journal of immunology.

[50]  J. Flynn,et al.  Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. , 1999, Journal of immunology.

[51]  Q. Hamid,et al.  The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells. , 1999, Journal of immunology.