Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection
Immunology & Microbiology
Department of Pathology
Medical Subject Headings
Acute Disease; Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; *Cell Proliferation; Influenza A virus; Interferon Regulatory Factors; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mice; Mice, Knockout; Orthomyxoviridae Infections; Receptors, Antigen, T-Cell; Signal Transduction; Up-Regulation
Cellular and Molecular Physiology | Immunology of Infectious Disease | Immunopathology
In response to acute virus infections, CD8(+) T cells differentiate to form a large population of short-lived effectors and a stable pool of long-lived memory cells. The characteristics of the CD8(+) T cell response are influenced by TCR affinity, Ag dose, and the inflammatory cytokine milieu dictated by the infection. To address the mechanism by which differences in TCR signal strength could regulate CD8(+) T cell differentiation, we investigated the transcription factor, IFN regulatory factor 4 (IRF4). We show that IRF4 is transiently upregulated to differing levels in murine CD8(+) T cells, based on the strength of TCR signaling. In turn, IRF4 controls the magnitude of the CD8(+) T cell response to acute virus infection in a dose-dependent manner. Modest differences in IRF4 expression dramatically influence the numbers of short-lived effector cells at the peak of the infection, but have no impact on the kinetics of the infection or on the rate of T cell contraction. Furthermore, the expression of key transcription factors such as T cell factor 1 and Eomesodermin are highly sensitive to graded levels of IRF4. In contrast, T-bet expression is less dependent on IRF4 levels and is influenced by the nature of the infection. These data indicate that IRF4 is a key component that translates the strength of TCR signaling into a graded response of virus-specific CD8(+) T cells.
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Citation: J Immunol. 2014 Jun 15;192(12):5881-93. doi: 10.4049/jimmunol.1303187. Epub 2014 May 16. Link to article on publisher's site
DOI of Published Version
Journal of immunology (Baltimore, Md. : 1950)
Nayar, Ribhu; Schutten, Elizabeth; Bautista, Bianca; Daniels, Keith A.; Prince, Amanda L.; Enos, Megan E.; Brehm, Michael A.; Swain, Susan L.; Welsh, Raymond M.; and Berg, Leslie J., "Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection" (2014). GSBS Student Publications. 1874.