Interferon regulatory factor-1 (IRF-1) shapes both innate and CD8(+) T cell immune responses against West Nile virus infection.

Abstract

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.

• Authors: James D Brien, Stephane Daffis, Helen M Lazear, Hyelim Cho, Mehul S Suthar, Michael Gale Jr, Michael S Diamond
• Journal: PLoS pathogens (PLoS Pathog) Vol. 7 Issue 9 Pg. e1002230 (Sep 2011) ISSN: 1553-7374 [Electronic] United States
• PMID: 21909274 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interferon Regulatory Factor-1
• Interferon-beta
• Interferon-gamma

Topics

• Adaptive Immunity (drug effects, immunology)
• Animals
• B-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Proliferation
• Central Nervous System (cytology)
• Immunity, Innate (drug effects)
• Interferon Regulatory Factor-1 (deficiency, immunology, physiology)
• Interferon-beta (physiology)
• Interferon-gamma (drug effects, physiology)
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• West Nile Fever (immunology)
• West Nile virus (immunology)