Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.
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-7Ralpha. 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-2Ralpha and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Ralpha repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Ralpha-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.
Pipkin
Matthew E
ME
Harvard Medical School, Boston, MA 02115, USA; Immune Disease Institute, Boston, MA 02115, USA.
Sacks
Jilian A
JA
Cruz-Guilloty
Fernando
F
Lichtenheld
Mathias G
MG
Bevan
Michael J
MJ
Rao
Anjana
A
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic
D007376:Interleukin-2