Priming of Natural Killer Cells by Nonmucosal Mononuclear Phagocytes Requires Instructive Signals from Commensal Microbiota

Abstract

Mononuclear phagocytes are an important component of an innate immune system perceived as a system ready to react upon encounter of pathogens.Here, we show that in response to microbial stimulation, mononuclear phagocytes residing in nonmucosal lymphoid organs of germ-free mice failed to induce expression of a set of inflammatory response genes, including those encoding the various type I interferons (IFN-I). Consequently, NK cell priming and antiviral immunity were severely compromised. Whereas pattern recognition receptor signaling and nuclear translocation of the transcription factors NF-kB and IRF3 were normal in mononuclear phagocytes of germ-free mice, binding to their respective cytokine promoters was impaired, which correlated with the absence of activating histone marks. Our data reveal a previously unrecognized role for postnatally colonizing microbiota in the introduction of chromatin level changes in the mononuclear phagocyte system, thereby poising expression of central inflammatory genes to initiate a powerful systemic immune response during viral infection.

The regulation of host defences to infection by the microbiota

“…This promotes viral eradication from the spleen. Again, the priming effect of the microbiota was mediated by PRR activation 68. Similarly, the microbiota enhances clearance of hepatitis B virus in the liver 72.…”

“…Because of the lack of direct contact with live microbes, it has long been presumed that the microbiota does not influence these systemic defences. We now know that this assumption is incorrect and that the production and function of cells that constitute systemic defences is greatly influenced by the microbiota 29, 30, 39, 66, 67, 68…”

“…Currently, the exact mechanisms of neutrophil killing promoted by the microbiota are unknown. Cytokine production by systemic macrophages and dendritic cell populations is also regulated by the microbiota 68. Reduced cytokine production by these cells in the spleen, particularly reduced type I interferon, leads to attenuated host defences against systemic viral infection 68.…”

“…Cytokine production by systemic macrophages and dendritic cell populations is also regulated by the microbiota 68. Reduced cytokine production by these cells in the spleen, particularly reduced type I interferon, leads to attenuated host defences against systemic viral infection 68. During systemic lymphocytic choriomeningitis virus infection, this microbiota‐dependent enhancement of type I interferon production by dendritic cells primes a more robust NK cell response 68.…”

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

“…For example, dental bacteria can cause episodic bacteremia and release LPS into the circulation and may also seed biofilm formation on orthopaedic implants [29,77,78]. Moreover, there is extensive evidence that PAMPs can translocate from the gastrointestinal tract to distant organs, including the bone marrow, and systemically prime the innate immune system in the absence of infection [14,18,25,28,42,63,70,71,84,101,115]. This translocation of PAMPs from the gut can be increased by minor surgical procedures, such as colonoscopy, a high-fat diet, or even a single high-fat meal [3,14,52,71,84].…”