Virus-Infected Human Mast Cells Enhance Natural Killer Cell Functions

Abstract

Mucosal surfaces are protected from infection by both structural and sentinel cells, such as mast cells. The mast cell's role in antiviral responses is poorly understood; however, they selectively recruit natural killer (NK) cells following infection. Here, the ability of virus-infected mast cells to enhance NK cell functions was examined. Cord blood-derivedhuman mast cells infected with reovirus (Reo-CBMC) and subsequent mast cell products were used for the stimulation of human NK cells. NK cells upregulated the CD69 molecule and cytotoxicity-related genes, and demonstrated increased cytotoxic activity in response to Reo-CBMC soluble products. NK cell interferon (IFN)-γ production was also promoted in the presence of interleukin (IL)-18. In vivo, SCID mice injected with Reo-CBMC in a subcutaneous Matrigel model, could recruit and activate murine NK cells, a property not shared by normal human fibroblasts. Soluble products of Reo-CBMC included IL-10, TNF, type I and type III IFNs. Blockade of the type I IFN receptor abrogated NK cell activation. Furthermore, reovirus-infected mast cells expressed multiple IFN-α subtypes not observed in reovirus-infected fibroblasts or epithelial cells. Our data define an important mast cell IFN response, not shared by structural cells, and a subsequent novel mast cell-NK cell immune axis in human antiviral host defense.

Interferon α2 and interferon γ induce the degranulation independent production of VEGF‐A and IL‐1 receptor antagonist and other mediators from human mast cells

“…Neither RSV, not reovirus induce significant short term degranulation of human mast cells, as we have previously reported. However both viruses induce substantial type 1 IFN responses at 24–48 h post infection 27, 28, 36.…”

“…Mammalian reovirus (type 3 Dearing) and RSV (serotype A, Long strain) were propagated, purified, and UV‐inactivated as previously described 28, 31, 32. UV inactivation was confirmed by standard plaque assay and flow cytometric analysis of virus treated cells.…”

“…CBMC (1 Â 10 6 /ml) in modified HEPES-Tyrode's buffer were treated for 20 min with increasing doses of IFNg or IFNa2 or calcium ionophore A23187 (0.5 mM), as a positive control. The level of degranulation was assessed via bhexosaminidase release according to the method of Schwartz et al [30] RSV and reovirus activation of CBMC Mammalian reovirus (type 3 Dearing) and RSV (serotype A, Long strain) were propagated, purified, and UV-inactivated as previously described [28,31,32]. UV inactivation was confirmed by standard plaque assay and flow cytometric analysis of virus treated cells.…”

“…It represents a useful model of effective anti-viral immunity. Reovirus-activated human mast cells secrete a wide range of type I IFNs [28,37]. To improve our understanding of the potential roles of mast cells as a source of IL-1Ra and VEGF during viral infection, we evaluated mast cell production of these mediators following a viral challenge.…”

“…IFNg has also been shown to enhance Fcg receptor expression [24,25] and both inflammatory and bacteriocidal activities of human mast cells in response to Gram positive bacteria [26]. In this study, we examined the impact of direct type I and type II IFN activation of human mast cells on cytokine and chemokine production relevant to inflammatory disease and the potential for selected IFN responses to be of importance in previously described human mast cell responses to viral infection [27,28].…”