NK Cell–Derived IFN-γ Protects against Nontuberculous Mycobacterial Lung Infection

Abstract

In developed countries, pulmonary nontuberculous mycobacteria (NTM) infections are more prevalent than infections. Given the differences in the pathogenesis of NTM and infections, separate studies are needed to investigate the pathological effects of NTM pathogens. Our previous study showed that anti-IFN-γ autoantibodies are detected in NTM-infected patients. However, the role of NK cells and especially NK cell-derived IFN-γ in this context has not been studied in detail. In the current study, we show that NK1.1 cell depletion increases bacterial load and mortality in a mouse model of pulmonary NTM infection. NK1.1 cell depletion exacerbates NTM-induced pathogenesis by reducing macrophage phagocytosis, dendritic cell development, cytokine production, and lung granuloma formation. Similar pathological phenomena are observed in IFN-γ-deficient (IFN-γ) mice following NTM infection, and adoptive transfer of wild-type NK cells into IFN-γ mice considerably reduces NTM pathogenesis. Injection of rIFN-γ also prevents NTM-induced pathogenesis in IFN-γ mice. We observed that NK cells represent the main producers of IFN-γ in the lungs and production starts as soon as 1 d postinfection. Accordingly, injection of rIFN-γ into IFN-γ mice 1 d (but not 2 wk) postinfection significantly improves immunity against NTM infection. NK cells also stimulate mycobacterial killing and IL-12 production by macrophages. Our results therefore indicate that IFN-γ production by NK cells plays an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary NTM infection.

Airway Natural Killer Cells and Bacteria in Health and Disease

“…The same observations were made in IFN-γ-KO animals and restored after transfer of wildtype NK cells. These cells were also the most important producer of IFN-γ in this model (86). Lai et al further cited papers that had demonstrated a similar protective effect of IFN-γ produced by NK cells in the infections with Bordetella pertussis, Francisella tularensis, and Chlamydia muridarum in mouse models of respiratory infection.…”

“…Lai et al (86) presented a work on nontuberculous mycobacterial lung infections, which means due to other mycobacterial species, such as Mycobacterium abscessus and Mycobacterium kansasii. As the latter become more and more prevalent in developed countries, these authors performed a study in C57BL/6 mice that were infected intratracheally with M. kansasii.…”

Phage therapy in antibiotic resistant pneumonia: immunomodulation or redistribution?

“…vate the resident elements of the immune system, and attract circulating immune cells to the lungs [7]. It was shown that the outcome of a pulmonary infection associated with Pseudomonas aeruginosa depends on the number of T helpers and the polarization of the immune response at their level [12], and NK cells are the main producers of IFNγ in the lungs and are rapidly activated for this purpose (within 1 day [11]). It is possible that the decrease in antigenic load in the respiratory tract, achieved immediately with successful phage therapy, reduces the need for these cellular elements, and an additional number of lymphocytes, including activated ones, appear in the peripheral blood.…”

Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines

“…We also recently showed that circulating NK cells are increased in abundance and mediate enhanced cytotoxic responses in latent Mtb infection, while a corresponding decrease during active disease was observed 68 . In addition, IFNγ production by NK cells was shown to play an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary non-tuberculous mycobacteria infection 69 .…”