article · Journal of Clinical Investigation
Some people living with HIV demonstrate natural resistance to Mycobacterium tuberculosis infection, remaining persistently negative on tuberculin skin tests and interferon-gamma release assays. Analysis of bronchoalveolar lavage cells from these individuals reveals distinctive lung immune profiles compared to individuals with latent tuberculosis infection. Alveolar macrophages from resistant individuals demonstrate a baseline M1 inflammatory phenotype. Furthermore, resistant individuals show increased lung lymphocytes, with an enrichment of all T cell subsets. A specific group of poly-cytotoxic T lymphocytes, which co-express granulysin, granzyme B, perforin, and activating natural killer cell receptors, is expanded in resistant lungs. Following laboratory exposure to the bacteria, macrophages from resistant individuals mount an early tumour necrosis factor response and uniquely upregulate MICA transcripts, which activate poly-cytotoxic T cells. These findings indicate that pre-activated macrophages and specialised cytotoxic T cells drive resistance to tuberculosis.
Tuberculosis remains a critical threat, particularly to people living with HIV. Understanding the biological mechanisms that allow certain individuals to resist infection despite high risk helps researchers identify which immune components protect the lungs. This knowledge clarifies natural defences against tuberculosis and guides future preventative strategies.
The findings represent early-stage biological discovery that could inform target discovery for future immunotherapies or tuberculosis vaccines. Research and development teams focused on pulmonary immunology or host-directed therapeutics could use these specific cellular phenotypes and pathways as reference biomarkers. However, the abstract indicates this is fundamental observational research that is still distant from clinical or commercial implementation.
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BACKGROUNDNatural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained.METHODSWe 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).RESULTSAlveolar 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.CONCLUSIONThese results suggest that poly-CTL and M1-like pre-activated AM mediate the resister phenotype in PWH.FUNDINGNational 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.
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DOI: 10.1172/jci188016
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