STAT1 Negatively Regulates Lung Basophil IL-4 Expression Induced by Respiratory Syncytial Virus Infection

Abstract

IL-4 contributes to immunopathology induced in mice by primary respiratory syncytial virus (RSV) infection. However, the cellular source of IL-4 in RSV infection is unknown. We identified CD3−CD49b+ cells as the predominant source of IL-4 in the lungs of RSV-infected BALB/c mice. We ruled out T cells, NK cells, NKT cells, mast cells, and eosinophils as IL-4 expressors in RSV infection by flow cytometry. Using IL4 GFP reporter mice (4get) mice, we identified the IL-4-expressing cells in RSV infection as basophils (CD3−CD49b+FcεRI+c-kit−). Because STAT1−/− mice have an enhanced Th2-type response to RSV infection, we also sought to determine the cellular source and role of IL-4 in RSV-infected STAT1−/− mice. RSV infection resulted in significantly more IL-4-expressing CD3−CD49b+ cells in the lungs of STAT1−/− mice than in BALB/c mice. CD49b+IL-4+ cells sorted from the lungs of RSV-infected STAT1−/− mice and stained with Wright-Giemsa had basophil characteristics. As in wild-type BALB/c mice, IL-4 contributed to lung histopathology in RSV-infected STAT1−/− mice. Depletion of basophils in RSV-infected STAT1−/− mice reduced lung IL-4 expression. Thus, we show for the first time that a respiratory virus (RSV) induced basophil accumulation in vivo. Basophils were the primary source of IL-4 in the lung in RSV infection, and STAT1 was a negative regulator of virus-induced basophil IL-4 expression.

NK Cell Deficiency Predisposes to Viral-Induced Th2-Type Allergic Inflammation via Epithelial-Derived IL-25

“…We observed that IL-4-producing basophils were specifically recruited to pulmonary lymph nodes in response to RSV infection, and this correlated with the development of Th2 cells. IL-4-secreting basophils have also been found in the parenchyma of STAT1 2/2 mice infected with RSV (48). However, depletion of basophils during exposure to RSV did not inhibit the development of viral-induced Th2 cells or features of allergic inflammation.…”

Differential Pathogenesis of Respiratory Syncytial Virus Clinical Isolates in BALB/c Mice

“…It is established in RSV vaccine-enhanced disease that T H 2 cells mediate immunopathology (68). In primary A2 strain RSV infection in mice, IL-4 suppresses IFN-␥ expression, promotes RSV-specific Ab production, and contributes to pulmonary mononuclear cell inflammation, but IL-4 deficiency has no effect on viral load, viral clearance, or disease severity (14,43). In primary A2 strain infection, IL-13 was shown to play a protective role in limiting viral load and disease severity (76).…”

“…Additional sections were stained with periodic acid-Schiff (PAS) stain to assess goblet cell hyperplasia as a measure of mucin expression. PAS-stained slides were digitally scanned using a Mirax Midi microscope with a 20ϫ objective having a 0.85 numerical aperture (Carl Zeiss Microimaging Inc., Thornwood, NY) (43). Areas of airway epithelium were annotated using HistoQuant software (3D Histech, Budapest, Hungary).…”

α-Galactosylceramide–Induced Airway Eosinophilia Is Mediated through the Activation of NKT Cells

“…CCR3 is highly expressed on eosinophils and a subset of T cells. Human basophils have been reported to express CCR3 in some studies (24); however, there is no CCR3 expression on mouse basophils (25,26). The frequency and absolute number of eosinophils in a-GalCer-administered wild-type mice were significantly increased compared with those in PBS controls.…”