Abstract
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), which leads to an estimated 1. 5 million deaths worldwide each year. Although the immune correlates of protection against Mtb infection and TB disease have not been well-defined, natural killer (NK) cells are increasingly recognized as a key component of the innate immune response to Mtb and as a link between innate and adaptive immunity. In this study, we evaluated NK cell phenotypic and functional profiles in QuantiFERON-TB (QFT)+ and QFT− adults in a TB endemic setting in Kisumu, Kenya, and compared their NK cell responses to those of Mtb-naïve healthy adult controls in the U.S. We used flow cytometry to define the phenotypic profile of NK cells and identified distinct CD56dim NK cell phenotypes that differentiated the Kenyan and U.S. groups. Additionally, among Kenyan participants, NK cells from QFT+ individuals with latent Mtb infection (LTBI) were characterized by significant downregulation of the natural cytotoxicity receptor NKp46 and the inhibitory receptor TIGIT, compared with QFT− individuals. Moreover, the distinct CD56dim phenotypic profiles in Kenyan individuals correlated with dampened NK cell responses to tumor cells and diminished activation, degranulation, and cytokine production following stimulation with Mtb antigens, compared with Mtb-naïve U.S. healthy adult controls. Taken together, these data provide evidence that the phenotypic and functional profiles of NK cells are modified in TB endemic settings and will inform future studies aimed at defining NK cell-mediated immune correlates that may be protective against acquisition of Mtb infection and progression to TB disease.
Highlights
Infection with Mycobacterium tuberculosis (Mtb) can lead to development of active tuberculosis (TB) disease, which is currently the leading cause of death in the world due to a single infectious agent (WHO Publication, 2018a)
In this study we evaluated the phenotypic and functional profiles of Natural killer (NK) cells from QFT+ and QFT− adults residing in a TB-endemic region in western Kenya, and compared those with NK cell profiles in Mtb-naïve, healthy adults from the U.S We demonstrated that CD56dim NK cells from Kenyan adults have distinct phenotypic profiles and attenuated responses following stimulation with MHC class I-devoid target cells and Mtb antigens, compared with U.S healthy adult controls
Within Kenyan adults, we found evidence of significant downregulation of NKp46 and TIGIT expression on CD56dim cells from QFT+ individuals with latent Mtb infection (LTBI), compared with QFT− individuals
Summary
Infection with Mycobacterium tuberculosis (Mtb) can lead to development of active tuberculosis (TB) disease, which is currently the leading cause of death in the world due to a single infectious agent (WHO Publication, 2018a). The only currently licensed TB vaccine, Mycobacterium bovis bacille Calmette-Guérin (BCG), provides variable efficacy, ranging from 0 to 80%, against pulmonary TB disease in adults (Andersen and Scriba, 2019). Both innate and adaptive immunity, including Mtb-specific T cell and antibody (Ab) responses, are clearly important in maintaining control of Mtb (Lu et al, 2016; Simmons et al, 2018), the precise immune correlates of protection to Mtb infection have not been well-defined. Longitudinal cohort studies have indicated that progression to active TB disease is preceded by a decline in the frequency of circulating NK cells, which is restored following successful treatment for active TB (Roy Chowdhury et al, 2018), providing further evidence of an important role for NK cells in Mtb infection and TB disease in humans
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