Interplay of innate and adaptive systems in influenza A infection and Pulmonary Inflammation: Role of Natural Killer cells

Abstract

Innate immunity is the first-line defense against pathogens. Recent studies demonstrate that innate immunity also plays a regulatory role. Natural Killer (NK) cells have been appreciated as effective killing machinery against infected and malignant cells for decades, but the regulatory roles of NK cells are still lacking. NK cells are one of the early defense mechanisms against influenza infection. An effective immune response against influenza A infection depends on the generation of virus-specific T cells. Hence, we set out to delineate the role of NK cells in T cell immunity using a murine model of influenza infection with A/PR/8/34. We showed that NK cells were activated during the early phase of infection. Depletion of NK cells significantly impaired pulmonary dendritic cell (DC) activation, migration into the posterior mediastinal lymph node (pMLN) and IL-12p70 production. Similarly, NK cells mediated naive and activated T cell recruitment to the pMLN mediated through IFN-? dependent chemokine expression as transfer of IFN-?+/+ naive NK cells into IFN-?-/- mice restored T cell recruitment while IFN-? deficient NK cells failed to do so. Additionally, NK cell depletion reduced uptake and transport of influenza virus by DCs via perforin and IFN-? dependent pathways, and hence, significantly impaired the virus-specific T cell response. To further understand the immune regulatory roles of NK cells on DC migration, we extend our study using a sterile inflammation model?ozone exposure. As pulmonary surfactant protein D has been shown to viii mediate DC migration and NKp46 is an activating receptor that mediates IFN-? production in NK cells, we set out to understand role of SP-D and NKp46 in NK cell regulation during ozone-induced lung inflammation. Post ozone exposure, migration of pulmonary DCs, expression of IFN-? especially derived from NK cells and CCL-21 were dampened. However, NKp46gfp/gfp (NKp46 deficient) mice showed no blockade of DC migration and reduction in NK cell derived IFN-? production suggesting that ozone actively suppresses DC migration by blocking NKp46 signaling. In SP-D-/- mice, pulmonary NK cells had reduced intracellular IFN-? expression and similar DC migration blockade compared to wild type mice. In contrast, treatment with recombinant SP-D increased IFN-g release from cultured splenocytes in vitro. SP-D-/- NKp46+/+ pulmonary NK cells dose dependently bound recombinant SP-D in while NKp46gfp/gfp pulmonary NK cell failed to do so. In summary, NK cells mediate both DC and T cell migration via IFN-? dependent pathways. SP-D is a likely regulator of lung resident NK cells promoting anti-inflammatory actions as well as host defenses through IFN-? release possibly through engaging NKp46. NK cells also promoted antigen uptake by DCs via perforin mediated cytotoxicity. Through these mechanisms, NK cells effectively regulate the ensuing innate and adaptive immunity against infection and inflammation.