Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli.

Abstract

Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained. We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were TST & IGRA positive (called LTBI) and 6 who were persistently TST & IGRA negative (called resisters). 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 co-expressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (CTL) over-expressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only Intraepithelial Lymphocytes-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6h post-infection while at 24h post-infection AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24h post-infection only AM from resisters displayed a significant upregulation of MICA transcripts which encode an activating ligand for poly-CTL. These results suggest that poly-CTL and AM mediate the resister phenotype in PWH.