1. Interleukin-2 and Inflammation Induce Distinct Transcriptional Programs that Promote the Differentiation of Effector Cytolytic T Cells
- Author
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Pipkin, Matthew E., Sacks, Jilian A., Cruz-Guilloty, Fernando, Lichtenheld, Mathias G., Bevan, Michael J., and Rao, Anjana
- Subjects
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INTERLEUKIN-2 , *TRANSCRIPTION factors , *CELL differentiation , *T cells , *CELL growth , *INFLAMMATION , *LYMPHOCYTES , *RNA polymerases - Abstract
Summary: Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression of memory CTL markers Bcl6 and IL-7Rα. Binding of Eomes and STAT5 to Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Rα and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Rα repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Rα-deficient effector CD8+ T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1+ and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development. [Copyright &y& Elsevier]
- Published
- 2010
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