Interleukin-2 and Inflammation Induce Distinct Transcriptional Programs that Promote the Differentiation of Effector Cytolytic T Cells.
Pipkin, Matthew E. 1,2,7; Sacks, Jilian A. 3,4,7; Cruz-Guilloty, Fernando 1,2,6,7; Lichtenheld, Mathias G. 5; Bevan, Michael J. 3,4; Rao, Anjana 1,2,*
[Article] Immunity. 32(1):79-90, January 2010.

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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-7R[alpha]. 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-2R[alpha] and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7R[alpha] repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2R[alpha]-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.

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