Human mast cell activation with virus-associated stimuli leads to the selective chemotaxis of natural killer cells by a CXCL8-dependent mechanism

Abstract

Human mast cells are found in skin and mucosal surfaces and next to blood vessels. They play a sentinel cell role in immunity, recognizing invading pathogens and producing proinflammatory mediators. Mast cells can recruit granulocytes, and monocytes in allergic disease and bacterial infection, but their ability to recruit antiviral effector cells such as natural killer (NK) cells and T cells has not been fully elucidated. To investigate the role of human mast cells in response to virus-associated stimuli, human cord blood-derived mast cells (CBMCs) were stimulated with polyinosinic⅐polycytidylic acid, a double-stranded RNA analog, or infected with the double-stranded RNA virus, reovirus serotype 3 Dearing for 24 hours. CBMCs responded to stimulation with polyinosinic⅐polycytidylic acid by producing a distinct chemokine profile, including CCL4, CXCL8, and CXCL10. CBMCs produced significant amounts of CXCL8 in response to low levels of reovirus infection, while both skin-and lungderived fibroblasts were unresponsive unless higher doses of reovirus were used. Supernatants from CBMCs infected with reovirus induced substantial NK cell chemotaxis that was highly dependent on CXCL8 and CXCR1. These results sug- IntroductionMast cells are long-lived resident tissue cells found close to blood vessels, and are numerous at sites in close proximity to the external environment such as the skin and airways (reviewed in Galli et al 1 and Metz and Maurer 2 ). From these strategic locations they can quickly recognize and respond to invading pathogens. They are also relatively resistant to ultraviolet (UV) and gamma irradiation. [3][4][5] Upon activation, mast cells produce a wide array of mediators, including granule-associated products, such as histamine, and preformed and de novo synthesized cytokines, chemokines, and lipid mediators. They can activate and recruit effector cells, including eosinophils, 6 neutrophils, 7 and monocytes. 8 Their role in innate immune responses to bacterial infections has been clearly delineated, however their involvement in viral infections is not well understood. Mast cells express Toll-like receptor 3 (TLR3), which recognizes viral double-stranded RNA (dsRNA), 9 and they can produce type I interferons when activated through this receptor. 10 Studies examining the permissiveness of mast cells to viruses show that they can be infected by, and respond to, dengue virus, 11,12 HIV, 13,14 and respiratory syncytial virus. 15 Human mast cells produce the chemokines CCL3, CCL4, and CCL5 when infected with dengue virus, 16 and mouse mast cells produce CCL4 and CCL5 when infected with Newcastle disease virus, all of which are known natural killer (NK) cell and T-cell chemoattractants. 17 NK cells are large granular lymphocytes that can kill virally infected cells, and are crucial for the clearance of viruses during infections (reviewed in Lodoen and Lanier 18 ). The chemokines and chemokine receptors necessary for the infiltration of NK cells into virally infected tissues have recently begun to be uncover...

Mast cell–macrophage dynamics in modulation of dengue virus infection in skin

“…15 Mast cells infected with several viruses including DENV produce a spectrum of chemokines that recruit specific leucocytes including natural killer (NK) cells. [16][17][18] In a mouse model of DENV infection, mast cells were implicated in recruitment of NK and NKT cells, which may clear virus. 18 RNA sensors, particularly RIG-I, enable human mast cell antiviral chemokine production and interferon-mediated protection in response to antibody-enhanced DENV infection.…”

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.…”

Mast cells are permissive for rhinovirus replication: potential implications for asthma exacerbations

“…by demonstrating an MOI‐dependent effect on virion release and induction of antiviral and pro‐inflammatory responses of the mature LAD2 cell line and primary MCs following infection with both a major and minor group HRV. The release of infectious HRV virions by MCs is in contrast to infection of MCs by other respiratory viruses including reovirus, RSV and IAV which are capable of infecting human MCs and inducing innate immune responses; however, there is little or no release of virus progeny 33, 38, 46. For instance, plaque assays of RSV infected CBMC supernatants confirm a lack of productive RSV infection of CBMCs 38.…”

“…Exposure of MCs to many different viruses including dengue virus, reovirus and RSV induces the release of cytokines and chemokines, which are speculated to recruit inflammatory cells to help clear the infection 33, 38, 57. In response to reovirus, MCs release CXCL8 which recruits NK cells 33 and CCL3‐5 which recruit a subsets of T cells 34 in vitro . Dengue virus infection of mice also results in MC‐dependent recruitment of NK and NKT cells, although the specific mediators involved were not investigated 58.…”