title: Protein kinase R is a novel mediator of CD40 signaling and plays a critical role in modulating immunoglobulin expression during respiratory syncytial virus infection.
abstract: Effective immunoglobulin responses play a vital role in protection against most pathogens. However, the molecular mediators and mechanisms responsible for signaling and selective expression of immunoglobulin types remain to be elucidated. Previous studies in our laboratory have demonstrated that protein kinase R (PKR) plays a crucial role in IgE responses to double-stranded RNA (dsRNA) in vitro. In this study, we show that PKR plays a critical role in IgG expression both in vivo and in vitro. PKR(-/-) mice show significantly altered serum IgG levels during respiratory syncytial virus (RSV) infection. IgG2a expression is particularly sensitive to a lack of PKR and is below the detection level in mock- or RSV-infected PKR(-/-) mice. Interestingly, we show that upon activation by anti-CD40 and gamma interferon (IFN-γ), B cells from PKR(-/-) mice show diminished major histocompatibility complex class II (MHC II), CD80, and CD86 levels on the cell surface compared to wild-type (WT) mice. Our data also show that PKR is necessary for optimal expression of adhesion molecules, such as CD11a and ICAM-1, that are necessary for homotypic aggregation of B cells. Furthermore, in this report we demonstrate for the first time that upon CD40 ligation, PKR is rapidly phosphorylated and activated, indicating that PKR is an early and novel downstream mediator of CD40 signaling pathways.
authors: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina, USA.
authors: Sheetal A
authors: SA
authors: Thakur
authors: Zachary B
authors: ZB
authors: Zalinger
authors: Teresa R
authors: TR
authors: Johnson
authors: Farhad
authors: F
authors: Imani
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D040881:CD11a Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D000914:Antibodies, Viral; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D040881:CD11a Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D018799:Intercellular Adhesion Molecule-1; D019892:eIF-2 Kinase