Interferon Regulatory Factor-1 (IRF-1) Shapes Both Innate and CD8+ T Cell Immune Responses against West Nile Virus Infection

PLoS Pathogens

Mehul S. Suthar¹  Michael Gale Jr.¹  Helen M. Lazear²  James D. Brien²  Stephane Daffis²  Michael S. Diamond²  Hyelim Cho³ 

[1] Department of Immunology, University of Washington, Seattle, Washington, United States of America;Departments of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America;Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America

关键词: T cells;    Cytotoxic T cells;    West Nile virus;    Viral replication;    Central nervous system;    Flow cytometry;    Neurons;    Spleen;   

DOI  :  10.1371/journal.ppat.1002230

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Interferon regulatory factor (IRF)-1 is an immunomodulatory transcription factor that functions downstream of pathogen recognition receptor signaling and has been implicated as a regulator of type I interferon (IFN)-αβ expression and the immune response to virus infections. However, this role for IRF-1 remains controversial because altered type I IFN responses have not been systemically observed in IRF-1-/- mice. To evaluate the relationship of IRF-1 and immune regulation, we assessed West Nile virus (WNV) infectivity and the host response in IRF-1-/- cells and mice. IRF-1-/- mice were highly vulnerable to WNV infection with enhanced viral replication in peripheral tissues and rapid dissemination into the central nervous system. Ex vivo analysis revealed a cell-type specific antiviral role as IRF-1-/- macrophages supported enhanced WNV replication but infection was unaltered in IRF-1-/- fibroblasts. IRF-1 also had an independent and paradoxical effect on CD8+ T cell expansion. Although markedly fewer CD8+ T cells were observed in naïve animals as described previously, remarkably, IRF-1-/- mice rapidly expanded their pool of WNV-specific cytolytic CD8+ T cells. Adoptive transfer and in vitro proliferation experiments established both cell-intrinsic and cell-extrinsic effects of IRF-1 on the expansion of CD8+ T cells. Thus, IRF-1 restricts WNV infection by modulating the expression of innate antiviral effector molecules while shaping the antigen-specific CD8+ T cell response.

【 授权许可】

CC BY