Abstract
Given the high mortality rate (>50%) and potential danger of intrapersonal transmission, highly pathogenic avian influenza (HPAI) H5N1 epidemics still pose a significant threat to humans. γδ T cells, which participate on the front line of the host immune defense, demonstrate both innate, and adaptive characteristics in their immune response and have potent antiviral activity against various viruses. However, the roles of γδ T cells in HPAI H5N1 viral infection remain unclear. In this study, we found that γδ T cells provided a crucial protective function in the defense against HPAI H5N1 viral infection. HPAI H5N1 viruses could directly activate γδ T cells, leading to enhanced CD69 expression and IFN-γ secretion. Importantly, we found that the trimer but not the monomer of HPAI H5N1 virus hemagglutinin (HA) proteins could directly activate γδ T cells. HA-induced γδ T cell activation was dependent on both sialic acid receptors and HA glycosylation, and this activation could be inhibited by the phosphatase calcineurin inhibitor cyclosporin A but not by the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294002. Our findings provide a further understanding the mechanism underlying γδ T cell-mediated innate and adoptive immune responses against HPAI H5N1 viral infection, which helps to develop novel therapeutic strategies for the treatment of H5N1 infection in the future.
Highlights
The highly pathogenic avian H5N1 influenza A virus poses a high risk for a global pandemic [1,2,3,4]
Our findings provide a further understanding the mechanism underlying γδ T cell-mediated innate and adoptive immune responses against highly pathogenic avian influenza (HPAI) H5N1 viral infection
These results demonstrate that a deficiency of γδ T cells results in a decreased survival rate and more severe lung injury following respiratory H5N1 infection, indicating that γδ T cells play a critical role in protection from H5N1 viral infection
Summary
The highly pathogenic avian H5N1 influenza A virus poses a high risk for a global pandemic [1,2,3,4]. Unlike αβ T cells, γδ T cells demonstrate both innate and adaptive characteristics in their immune response and have potent antiviral activity against different viruses, including influenza A virus [10, 11], human immunodeficiency virus (HIV) [12], cytomegalovirus (CMV) [13], and herpes simplex virus 1 (HSV-1) [14]. Recent studies demonstrated that γδ T cells expanded by the phosphoantigen isopentenyl pyrophosphate (IPP) were able to kill monocyte-derived macrophages infected by human (H1N1) and avian (H9N2 or H5N1) influenza viruses [15, 16]. The interaction between human γδ T cells and highly pathogenic avian influenza (HPAI) H5N1 viruses remains poorly understood. No reports of the direct effects of HPAI H5N1 viruses on human γδ T cells are yet available
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