Functional and Phenotypic Changes of Natural Killer Cells in Whole Blood during Mycobacterium tuberculosis Infection and Disease

Abstract

Tuberculosis (TB) is still a global health concern, especially in resource-poor countries such as The Gambia. Defining protective immunity to TB is challenging: its pathogenesis is complex and involves several cellular components of the immune system. Recent works in vaccine development suggest important roles of the innate immunity in natural protection to TB, including natural killer (NK) cells. NK cells mediate cellular cytotoxicity and cytokine signaling in response to Mycobacterium tuberculosis (Mtb). NK cells can display specific memory-type markers to previous antigen exposure; thus, bridging innate and adaptive immunity. However, major knowledge gaps exist on the contribution of NK cells in protection against Mtb infection or TB. We performed a cross-sectional assessment of NK cells phenotype and function in four distinct groups of individuals: TB cases pre-treatment (n = 20) and post-treatment (n = 19), and household contacts with positive (n = 9) or negative (n = 18) tuberculin skin test (TST). While NK cells frequencies were similar between all groups, significant decreases in interferon-γ expression and degranulation were observed in NK cells from TB cases pre-treatment compared to post-treatment. Conversely, CD57 expression, a marker of advanced NK cells differentiation, was significantly lower in cases post-treatment compared to pre-treatment. Finally, NKG2C, an activation and imprinted-NK memory marker, was significantly increased in TST+ (latently infected) compared to TB cases pre-treatment and TST− (uninfected) individuals. The results of this study provide valuable insights into the role of NK cells in Mtb infection and TB disease, demonstrating potential markers for distinguishing between infection states and monitoring of TB treatment response.

Distinct Human NK Cell Phenotypes and Functional Responses to Mycobacterium tuberculosis in Adults From TB Endemic and Non-endemic Regions

“…NK cells are recruited to the lung in patients with active TB disease (Portevin et al, 2012). However, NK cells circulating in peripheral blood of patients with pulmonary TB disease exhibit decreased IFN-γ production capacity (Bozzano et al, 2009;Garand et al, 2018), which is partially restored following anti-TB treatment (Nirmala et al, 2001), thus suggesting an association between NK cell functional capacity and bacterial load. Moreover, 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), thus providing further evidence of an important role for NK cells in Mtb infection and TB disease in humans.…”

Thinking Outside the Box: Innate- and B Cell-Memory Responses as Novel Protective Mechanisms Against Tuberculosis

“…In humans, NK cells can be found in lung tissue specimens from patients with chronic Mtb infection (78), suggesting their involvement in TB pathogenesis. Current evidence suggests a beneficial role of NK cells during human TB as changes in their immunophenotype and function are associated with the development of active TB (79)(80)(81)(82)(83)(84)(85)(86)(87)(88). NK cells support the activity of CD8+ T cells during Mtb infection (89), shape the maturation process and Mtb-antigen processing in dendritic cells (DCs) (90), limit the expansion of regulatory CD25+ T cells (91), and even participate in the mechanisms underlying protection induced by BCG vaccination (92).…”

HLA-E: exploiting pathogen-host interactions for vaccine development

“…NK cells form a substantial part of the innate immune response generated from this vaccine, and produce inflammatory cytokines in response to infection [63]. Although understanding of NK cell function during Mycobacteria infection is limited, NK cells in the Mtb granuloma exert cytotoxic pressure through production of granulysin and perforin [64], as well as restriction of bacterial growth through direct contact with infected cells via cytotoxic NKG2D + NK cells [32]. HLA-E : Mtb peptide complexes are not recognized by CD94/NKG2 molecules, so do not control activation or inhibition of NK cells through these receptors [65].…”