The Immunoregulatory Role of Natural Killer (NK) Cell Derived IL-10 During Microbial Infections

Abstract

Natural Killer (NK) cells, lymphocytes of the innate immune response, play a vital role in controlling infections and in tumor surveillance. NK cells provide protection by direct cytolysis of infected cells and by the production of pro-inflammatory cytokines such as, IFN-γ and TNF-α. Notably, NK cells have recently been identified to regulate the immune response by producing the anti-inflammatory cytokine IL-10. Several other cells can produce IL-10 during infections, however NK cell derived IL-10 can be critical in regulating immune response during early phases of infection and therefore protecting the host from excessive immunopathology. Although the regulatory role of NK cells seems to be plausible, the physiological relevance of NK cell mediated immune regulation during infections has not been demonstrated in detail. To investigate the immunoregulatory function of NK cells, I used Murine Cytomegalovirus (MCMV) infection induced by a high dose challenge and demonstrated that NK cells are a major IL-10 producer during acute stage of the infection. To elucidate the role of NK cell derived IL-10 during infections, I generated NK cell specific IL-10 knockout, NKp46iCre  Il-10flox/flox mice (NK-Il-10-/-) by crossing Il-10flox/flox mice with mice expressing Cre recombinase exclusively under the NK cell specific promoter, NKp46 (NKp46iCre knock-in mice). My results indicated that Cre mediated Il-10 genomic deletion occurred predominantly in NK cells but not in NKT, T and B cells. Enriched NK cells from NK-Il-10-/- mice failed to produce IL-10 upon ex vivo IL-2/IL-12 stimulation. Furthermore, histological analysis of the colon indicated that NK-Il-10-/- mice are free from aberrant inflammation. During sustained MCMV infection, significantly higher production of IFN-γ by CD8+ T cells of NK-Il-10-/- mice in salivary glands indicates that NK cell derived IL-10 contributes to the establishment of the immune suppressive environment in the organ. NK-Il-10-/- mice also demonstrated increased susceptibility to acute Listeria monocytogenes (LM) infection based on enhanced body weight loss. Taken together, I have successfully generated NK-Il-10-/- mice that lack the Il-10 gene exclusively in NK cells. The NK-Il-10-/- mouse can be used as an ideal model to dissect the immunoregulatory role of NK cells during various microbial infections and tumorogenesis.