NK cell determinants of immunity to mycobacterium tuberculosis in humans

Young-Bailie, Carly

NK cell determinants of immunity to mycobacterium tuberculosis in humans

Thesis / Dissertation

2023

Abstract

Natural killer (NK) cells are highly equipped responders to pathogen-infected and neoplastic cells by directly killing target cells and secreting immunoregulatory cytokines. Our understanding of the role of NK cells in TB pathogenesis remains incomplete. This thesis aimed to investigate the functional role of NK cells during progression to TB disease and to characterize NK subsets across human tissues in TB and healthy controls. In this thesis, NK cells were studied in a cohort of Mtb-infected adolescents who were followed up over two years. Using mass cytometry, results showed that cytokine responses by NK cells in the peripheral blood were lower at distal timepoints but increased significantly with time to diagnosis in those who progressed to TB, compared to those who controlled Mtb infection. Functional investigation using a flow cytometry cytokine neutralization assay suggested that peripheral blood NK cell function and cytotoxic potential during TB disease was dependent on T cell bystander activation. Despite important findings in peripheral blood, the TB field lacks a comprehensive understanding of phenotypic and functional characteristics of NK cells in human tissues, where the disease mostly manifests. To address this gap, human NK cells were characterized in a cohort of TB patients who succumbed to disease, and controls who were apparently healthy but died from trauma. Using postmortem samples from peripheral blood, lung, hilar lymph nodes, bronchoalveolar lavage (BAL), and spleen, NK cell phenotypes and cytotoxic potential were characterized by mass cytometry. Results showed that NK cells in the peripheral blood of TB patients displayed predominantly mature, activated phenotypes, expressing higher levels of cytotoxic molecules in TB than those from healthy controls. In contrast, NK cells in tissues, including lungs, hilar lymph nodes, BAL, and spleen were phenotypically immature and lacked expression of maturation markers and cytotoxic molecules. Immature NK cells with low cytotoxic potential were particularly enriched in the TB lung relative to controls. Further investigation into the functional capacity of immature lung NK cells that accumulate during TB disease may reveal mechanistic targets for clinical interventions. This thesis delves into the complex phenotypic and functional characteristics of NK cells, offering insights into tissue immunology in the context of TB disease. The findings presented herein have relevance in immunopathogenesis and development of new interventions, such as vaccines.

Keywords

Pathology

Reference:

Collections

PhD / Doctoral

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