Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli
Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr
Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr
Published January 21, 2025
Citation Information: J Clin Invest. 2025;135(7):e188016. https://doi.org/10.1172/JCI188016.
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Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli

Abstract

BACKGROUND Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained.METHODS We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were tuberculin skin test (TST) and IFN-γ release assay (IGRA) positive (called LTBI) and 6 who were persistently TST and IGRA negative (called resisters).RESULTS Alveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that coexpressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (poly-CTL) overexpressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only intraepithelial lymphocyte-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6 hours after infection while at 24 hours after infection, AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24 hours after infection, only AM from resisters displayed an upregulation of MHC class I polypeptide–related sequence A (MICA) transcripts, which encode an activating ligand for poly-CTL.CONCLUSION These results suggest that poly-CTL and M1-like pre-activated AM mediate the resister phenotype in PWH.FUNDING National Institutes of Health. Canadian Institutes of Health Research. Digital Research Alliance of Canada. French National Research Agency. French National Agency for Research on AIDS and Viral Hepatitis. St. Giles Foundation. General Atlantic Foundation. South African Medical Research Council Centre for Tuberculosis Research.

Authors

Monica Dallmann-Sauer, Vinicius M. Fava, Stephanus T. Malherbe, Candice E. MacDonald, Marianna Orlova, Elouise E. Kroon, Aurélie Cobat, Stéphanie Boisson-Dupuis, Eileen G. Hoal, Laurent Abel, Marlo Möller, Jean-Laurent Casanova, Gerhard Walzl, Nelita Du Plessis, Erwin Schurr

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Figure 1

Resisters have higher lymphocyte proportions in cells obtained by BAL compared with LTBI.

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Resisters have higher lymphocyte proportions in cells obtained by BAL co...
(A) Schematic representation of the study design. BAL cells were obtained from all study participants and scRNA-Seq was conducted at 6 hours and 24 hours in the presence and absence of Mtb infection. Gene-expression data were derived both for uninfected (defined as baseline) and infected BAL cells. Analysis of scRNA-Seq data was used to estimate BAL cell identities and proportions and to perform DE analysis. Created with BioRender.com. (B) UMAP of the scRNA-Seq data from the BAL cells of all subjects identified myeloid cells and lymphocytes as 2 main populations. (C) Gene expression of canonical markers for macrophages (LYZ and CD68), DCs (LAMP3), leukocytes (PTPRC [CD45]), T cells (CD3D), and B cells (MS4A1). Higher expressions are shown by darker colors in the UMAP. (D) Density of cells obtained from LTBI and resister participants. Dashed-line circles indicate the BAL lymphocytes in the 2 groups. Yellow and dark blue colors indicate the highest and lowest density of cells in the UMAP, respectively. UMAPs included samples irrespective of infection status and incubation time point. (E) Box plot of lymphocyte proportions (%) in BAL cells obtained from resister and LTBI participants. Each dot represents the average lymphocyte percentage obtained from the scRNA-Seq libraries per subject. (F) Lymphocyte proportion (%) in PBMCs for the same resister and LTBI participants.