NK cells inhibit anti-Mycobacterium bovisBCG T cell responses and aggravate pulmonary inflammation in a direct lung infection mouse model

Abstract

Tuberculosis remains a threat to public health. The major problem for curing this disease is latent infection, of which the underlying mechanisms are still not fully understood. Previous studies indicate that natural killer (NK) cells do not play a role in inhibiting the growth of Mycobacterium tuberculosis in the lung, and recent studies have revealed that NK cells regulate the adaptive immunity during mycobacterial infection. By using a mouse model of direct lung infection with Mycobacterium bovis bacillus Calmette-Guerin (BCG), we found that the presence of NK cells postponed the priming and activation of T cells after BCG infection. In addition, depletion of NK cells before infection alleviated pulmonary pathology. Further studies showed that NK cells lysed BCG-infected macrophages in an NKG2D dependent manner. Thus, NK cells did not play a direct role in control BCG, but aggravated the pulmonary inflammation and impaired anti-BCG T cell immunity, likely through killing BCG-infected macrophages. Our results may have important implications for the design of immune therapy to treat tuberculosis.

Airway Natural Killer Cells and Bacteria in Health and Disease

“…Bacillus Calmette-Guérin-infected macrophages up-regulated NKG2D ligands, which induced their lysis via this receptor-ligand interaction. Finally, the blocking of NKG2D with a monoclonal antibody restored the survival of the macrophages and the T cell-mediated immune response (89).…”

“…Some studies were also performed on Mycobacterium bovis Bacillus Calmette-Guérin (BCG), an attenuated mycobacterial strain used as an anti-tuberculous vaccine ( 89 ). For example, it was demonstrated in vitro that CD56 bright NK cells reacted to this microorganism by proliferation and IFN-γ production, whereas their CD56 dim counterparts better up-regulated the cytolytic proteins perforin and granzyme A ( 90 ), all of which was largely expected based on what is known about the functional specialization of these two NK cell subsets ( 1 – 3 ).…”

“…For example, it was demonstrated in vitro that CD56 bright NK cells reacted to this microorganism by proliferation and IFN-γ production, whereas their CD56 dim counterparts better up-regulated the cytolytic proteins perforin and granzyme A ( 90 ), all of which was largely expected based on what is known about the functional specialization of these two NK cell subsets ( 1 – 3 ). In a mouse in vivo model, where BCG was directly administered (intratracheally) into the lungs, NK cell-mediated production of IFN-γ rapidly increased in the first days after infection, similarly to the number of lung NK cells ( 89 ). After NK cell depletion, the reduction of body weight was less pronounced compared to non-depleted mice, whereas the bacterial load remained identical.…”

Cheap and Commonplace: Making the Case for BCG and γδ T Cells in COVID-19

“…Tu et al., expanded Vδ2 cells in vitro with the NBP pamidronate (PAM) and injected them into influenza infected humanized mice, demonstrating an improvement in disease severity and control of viral replication ( 110 ). Studies have also shown the NKG2D ligand MICA to be upregulated on epithelial and DCs after M. tb in humans ( 111 ), and mice NKG2D ligands Rae-2 and MULT1 are upregulated after BCG infection in the murine model ( 112 ).…”

CD28 Deficiency Ameliorates Blast Exposure-Induced Lung Inflammation, Oxidative Stress, Apoptosis, and T Cell Accumulation in the Lungs via the PI3K/Akt/FoxO1 Signaling Pathway

“…In addition to inflammation, blast exposure also induced oxidative stress [6, 7] and apoptosis [8] in the lungs of experimental animals. Recent studies reported that T cell activation had a pivotal role in the development of inflammation [9, 10]. At least two signals are required for the full activation of T cells.…”