[R01] Evaluating human T cells specific for Mycobacterium tuberculosis antigens that are processed and presented by infected macrophages
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2030-07-31
Importo max: 809.468 EUR
Paese: US
Descrizione
Tuberculosis (TB) remains the leading cause of death from a single infectious disease. In the United States, approximately 13 million people carry latent Mycobacterium tuberculosis (Mtb) infection (LTBI), and active TB cases have risen for four consecutive years to over 10,000 in 2024. Emerging data indicate that direct T cell recognition of Mtb-infected macrophages, the niche cell for Mtb infection, is central to a protective immune response. The premise of this proposal is that identifying the antigens processed and presented by Mtb-infected macrophages, and the T cell repertoire that target these antigens, is essential to designing vaccines that prevent active TB. The high TB burden in Kampala, Uganda, coupled with our longstanding collaboration for TB research provided a unique household contact (HHC) cohort, followed since 2002, in which new Mtb infection is captured in real time by IGRA conversion. This established study and clinical setting are not efficient or feasible in the U.S. where outbreaks are sporadic. Because the antigens and T cell responses that emerge during natural Mtb acquisition define what a protective vaccine must elicit, this Ugandan cohort directly informs vaccine design for use in the U.S., where TB remains an NIH/CDC priority and domestic cases continue to rise. Our study previously enrolled asymptomatic IGRA-negative HHCs to capture new “converters” (CVTR), alongside stable IGRApositive HHCs (LTBI) and IGRA-negative “nonconverters” (NCVTR). T cells and macrophages from blood and bronchoalveolar lavage (BAL) of CVTRs form the basis of our proposed longitudinal studies. The experimental approach for this proposal builds on two complementary, ongoing lines of investigation. Using mass spectrometry across diverse HLA alleles in Mtb-infected cells, we found that peptides from CFP10 (an ESX1 substrate absent from BCG) were presented by all MHC-II alleles tested, while other antigens were only found in the context of certain MHC-II alleles. Using single-cell RNA sequencing (scRNAseq) with T antigen cell receptor (TCR) mapping, we found Mtb-specific CD4+ T cell recognition of infected macrophages varies with macrophage phenotype and T cell specificity. Leveraging our team’s combined expertise, we will define the antigens presented by Mtb-infected macrophages and compare Mtb-specific T cell responses at early vs. late time points after IGRA conversion, in peripheral blood and lung. Aim 1 uses immunopeptidomics to identify Mtb antigens on infected macrophages and enumerates circulating CD4+ T cells specific for these antigens after conversion. Aim 2 uses scRNAseq to define the TCR repertoire, specificity, and function of T cells from BAL and blood, longitudinally, after IGRA conversion. In Aim 3 we will compare the capacities to control bacterial growth among human CD4+ T cells that target antigens presented by Mtb-infected monocyte-derived and alveolar macrophages (vs. other immunodominant Mtb antigens). The antigens, TCRs,
Istituzione: CASE WESTERN RESERVE UNIVERSITY
PI: Stephen Matthew Carpenter
Progetto: 5R01AI187662-02
Settori: National Institute of Allergy and Infectious Diseases
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