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Principal Investigator: Daniel F. Hoft
Organization: SAINT LOUIS UNIVERSITY
Fiscal Year: 2024
Award: $667,594
Funding agency: National Institute of Allergy and Infectious Diseases
-γ-producing Th1 cells have been extensively studied for development of novel vaccines and therapeutics against Mycobacterium tuberculosis (Mtb) infection. However, recent studies demonstrate that Mtb-specific Th1 cells alone do not predict protection against tuberculosis (TB). Therefore, although Th1 cells are required for controlling Mtb replication, other types of immune cells may be needed to prevent infection and eradicate the bacteria. We recently found that a subset of IL-9-producing CD4+ T cells (Th9) can mediate protective immunity against Mtb infection. Th9 cells can be differentiated from naïve CD4+ T cells with TGF-β and IL-4, and play important roles in antitumor immunity and immunity related to allergic reactions. The role of Th9 cells in Mtb infection, however, remain largely unknown. We discovered a role for Th9 cells in TB immunity when we analyzed the transcriptomes in CD4+ T cells from healthy volunteers vaccinated with BCG and from people with latent TB infection (LTBI). IL-9 mRNA in CD4+ T cells topped the list of genes increased after BCG vaccination and LTBI. A significant increase in IL-9 production by bronchoalveolar lavage (BAL) cells after stimulation with infectious Mtb was observed only in LTBI patients and people vaccinated with oral (PO) BCG, indicating induction of Mtb-specific Th9 memory responses. To test whether Th9 cells mediate intracellular Mtb killing, we differentiated Mtb-specific Th9 cells from ESAT6-TCR transgenic mice and co-cultured these Th9 cells with Mtb-infected murine macrophages. Intracellular mycobacterial growth was significantly reduced in macrophages after interacting with Th9 cells. Moreover, neutralizing IL-9 abolished the inhibitory effects of Th9 cells, while addition of recombinant IL-9 alone inhibited intracellular bacterial growth. Furthermore, adoptive transfer of Mtb-specific Th9 cells into syngeneic RAG1/2-/- mice suppresses Mtb growth in vivo. In addition, we found that IL-9 was increased and Mtb growth decreased in mice deficient in MCPIP1, a new RNA-binding protein affecting T cell activation. Deletion of MCPIP1 in Th9 cells resulted in a significantly enhanced IL-9 production upon restimulation. Based on our preliminary findings, we hypothesize that Mtb-specific Th9 cells represent a distinct subset of CD4+ T cells important for protective TB immunity. Strategies inducing Mtb- specific Th9 cells could be used to develop more effective TB vaccines and/or immunotherapies. We propose three aims to test this novel hypothesis: Aim 1 to determine the effects of Mtb-specific Th9 cells on protective TB immunity; Aim 2 to define the roles of IL-9 in vaccine-induced protection against Mtb infection using genetically engineered mice, and Aim 3 to identify the source for IL-9 in PBMC and BAL cells from BCG vaccinated individuals, and the mechanisms of Mtb-specific Th9 cell-mediated bacterial killing in human macrophages. These studies will have a significant impact on improving our understanding of host protective immune mechanisms against Mtb infection, and provide the rationale for targeting Mtb-specific Th9 cells as a new strategy for more effective TB vaccines and/or immunotherapies against Mtb infection.
Terms: <Adoptive Transfer><Affect><Allergic Reaction><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><BCDF-1><BCG Vaccine><BCG immunization><BCG vaccination><BCG-vaccinated><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Bacille Calmette Guerin vaccine><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacillus Calmette Guerin Vaccine><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Bacillus Calmette-Guérin vaccine><Bacteria><Binetrakin><Blood><Blood Reticuloendothelial System><Bone-Derived Transforming Growth Factor><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Co-culture><Cocultivation><Coculture><Coculture Techniques><Data><Development><Disease><Disorder><GEM model><GEMM model><Generalized Growth><Genes><Genetically Engineered Mouse><Growth><HP40><Helminths><Homolog of Mouse T Cell and Mast Cell Growth Factor 40><Human><IFN><IL-4><IL-9><IL4 Protein><IL9 Protein><Immune><Immune mediated therapy><Immunes><Immunity><Immunologically Directed Therapy><Immunotherapy><Infection prevention><Inflammation><Inflammatory><Interferons><Interleukin 9 Precursor><Interleukin-4><Interleukin-4 Precursor><Interleukin-9><Intravenous><KO mice><Knock-out Mice><Knockout Mice><Lung><Lung Lavage><Lung Respiratory System><Lymphocyte Stimulatory Factor 1><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MCGF-2><MTB infection><MTB vaccine><Macaca><Macaque><Macrophage><Mast Cell Growth Factor-2><Mediating><Memory><Messenger RNA><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Monocyte Chemoattractant Proteins><Monocyte Chemotactic Proteins><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mφ><Null Mouse><Oral><PBMC><Parasites><Parasitic Worms><Patients><Peripheral Blood Mononuclear Cell><Persons><Platelet Transforming Growth Factor><Play><Prevent infection><Production><Proteins><RNA-Binding Proteins><Recombinants><Reporter><Reporting><Role><Route><Sampling><Source><Subcellular Process><T-Cell Activation><T-Cell Growth Factor 2><T-Cell Growth Factor P40><T-Cell/Mast Cell Growth Factor p40><T4 Cells><T4 Lymphocytes><TB immunity><TB infection><TB vaccine><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Th-1 Cell><Th1 Cells><Tissue Growth><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transgenic Mice><Tuberculosis><Tuberculosis Vaccines><Tumor Immunity><Type 1 Helper Cell><Vaccinated><Vaccination acquired immunity><Vaccination induced immunity><Vaccine for TB><Vaccine for Tuberculosis><Vaccinee><Vaccines><activate T cells><anti-TB vaccine><anti-tumor immunity><antitumor immunity><bronchopulmonary lavage therapy><cancer immunity><cell type><cytokine><developmental><disseminated TB><disseminated tuberculosis><genetically engineered mouse model><genetically engineered murine model><global gene expression><global transcription profile><healthy volunteer><human subject><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunity against M. tuberculosis><immunity against Mtb><immunity against Mycobacterium tuberculosis><immunity against TB><immunity against tuberculosis><immunity in tuberculosis><immunity to TB><immunity to tuberculosis><immuno therapy><improved><in vivo><indicated prevention><indicated preventive interventions><indicated preventive measure><infection due to Mycobacterium tuberculosis><mRNA><mtb><mycobacterial><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><new vaccines><next generation therapeutics><next generation vaccines><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><novel vaccines><ontogeny><p40 Cytokine><p40 Protein><prevention directed at individuals><protective effect><pulmonary><response><social role><transcriptome><tuberculosis immunity><tuberculosis infection><tuberculous spondyloarthropathy><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine acquired immunity><vaccine against M. tuberculosis><vaccine against Mtb><vaccine against Mycobacterium tuberculosis><vaccine against TB><vaccine against tuberculosis><vaccine associated immunity><vaccine candidates against tuberculosis><vaccine-induced immunity><vaccine-induced protection>