Biology subjects

Ogongo, P.

Publications and source records attributed to Ogongo, P..

5 recordsLinked to original sources

bioRxiv2025

Evolution of T cell responses in the tuberculin skin test reveals generalisable Mtb-reactive T cell metaclones.

T cells contribute to immune protection and pathogenesis in tuberculosis, but measurements of polyclonal responses have failed to resolve correlates of outcome. We report the first temporal evaluation of the human in vivo clonal repertoire of Mtb-reactive T cell responses, by T cell receptor (TCR) sequencing at the site of a standardised antigenic challenge. Initial recruitment of non-Mtb reactive T cells is followed by enrichment of Mtb-reactive clones arising from oligoclonal T cell proliferation. We introduce a modular computational pipeline, Metaclonotypist, to sensitively cluster distinct TCRs with shared epitope specificity, which we apply here to establish a catalogue of public Mtb-reactive HLA-restricted T cell metaclones. Although most in vivo Mtb-reactive T cells are private, 10 metaclones were sufficient to identify Mtb-T cell reactivity across our study population (N[≥]128), indicating striking population level immunodominance of specific TCR-peptide interactions that may offer novel approaches to patient stratification and vaccine development.

immunology↗

bioRxiv2024

Integrated, high-dimensional analysis of CD4 T cell epitope specificities and phenotypes reveals unexpected diversity in the response to Mycobacterium tuberculosis

Immunity to Mycobacterium tuberculosis (Mtb), like many pathogens, is encoded jointly by the antigen specificities and functions of responding CD4 T cells. However, these features span a large two-dimensional possibility space - defined on one axis by the Mtb proteome, and on the other by the T cell transcriptome - that exceeds the dimensionality of existing technologies. Here we present an approach ("CRESTA") that combines highly-multiplexed DNA-barcoded epitope probes, single cell sequencing, and clonal analysis of T Cell Receptors (TCRs) to robustly detect rare antigen-specific CD4 T cells across hundreds of epitopes simultaneously and reveal their transcriptome-wide phenotypes. By comprehensively assaying known epitopes in Mtb-infected participants, we reveal polyclonal and multi-epitope responses across a spectrum of differentiation states, uncover previously-unobserved phenotypic diversity within and between epitopes, and increase the total number of known Mtb epitope-mapped TCR:{beta}s by [~]8-fold. We expect CRESTA to enable high-dimensional analyses of CD4 T cell responses in various settings, including infection, cancer, autoimmunity and allergy.

immunology↗

bioRxiv2024

Immunopeptidomics informs discovery and delivery of Mycobacterium tuberculosis MHC-II antigens for vaccine design

No currently licensed vaccine reliably prevents pulmonary tuberculosis (TB), a leading cause of infectious disease mortality. Developing effective new vaccines will require identifying which of the roughly 4000 proteins in the Mycobacterium tuberculosis (Mtb) proteome are presented on MHC class II (MHC-II) by infected human phagocytes and can be recognized by CD4+ T cells to mediate protective immunity. Vaccines must also elicit T cell responses recognizing the same peptide-MHC complexes presented by infected cells, and successful presentation of target human MHC-II peptides is currently challenging to evaluate and optimize. Here, we define antigenic targets for TB vaccine development by using mass spectrometry (MS) for proteome-wide discovery of Mtb epitopes presented on MHC-II by infected human cells. We next iteratively design and evaluate candidate mRNA vaccine immunogens, revealing design principles that enhance presentation of target MHC-II peptides. Our results will inform the development of new TB vaccine candidates.

microbiology↗

bioRxiv2024

Rare Variable M. tuberculosis Antigens induce predominant Th17 responses in human infection

CD4 T cells are essential for immunity to M. tuberculosis (Mtb), and emerging evidence indicates that IL-17-producing Th17 cells contribute to immunity to Mtb. While identifying protective T cell effector functions is important for TB vaccine design, T cell antigen specificity is also likely to be important. To identify antigens that induce protective immunity, we reasoned that as in other pathogens, effective immune recognition drives sequence diversity in individual Mtb antigens. We previously identified Mtb genes under evolutionary diversifying selection pressure whose products we term Rare Variable Mtb Antigens (RVMA). Here, in two distinct human cohorts with recent exposure to TB, we found that RVMA preferentially induce CD4 T cells that express RoR{gamma}t and produce IL-17, in contrast to classical Mtb antigens that induce T cells that produce IFN{gamma}. Our results suggest that RVMA can be valuable antigens in vaccines for those already infected with Mtb to amplify existing antigen-specific Th17 responses to prevent TB disease.

immunology↗

bioRxiv2023

M. tuberculosis antigen-responsive IL17+ CD4 T cells are disproportionately spared in ART-suppressed HIV

BackgroundInterleukin 17 producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with Human Immunodeficiency Virus (HIV) disproportionately affects distinct Th17 cell subsets that respond to Mtb is incompletely defined. MethodsWe performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by LC/MS on plasma and tested the hypothesis that tryptophan catabolism influences Th17 cell frequencies in this context. ResultsWe identified two subsets of Th17 cells: subset 1 defined as CD4+V7.2-CD161+CD26+ and subset 2 defined as CD4+V7.2-CCR6+CXCR3- cells of which subset 1 was significantly reduced in LTBI with HIV-ART, yet Mtb-responsive IL17-producing CD4 T cells were preserved; we found that IL17-producing CD4 T cells dominate the response to Mtb antigen but not CMV antigen or staphylococcal enterotoxin B (SEB); and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17 cell frequencies. ConclusionsWe found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.

immunology↗