Interleukin-2 and Inflammation Induce Distinct Transcriptional Programs that Promote the Differentiation of Effector Cytolytic T Cells

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.

Efficiency of diagnostic biomarkers among colonic schistosomiasis Egyptian patients

“…Stavitsky and Harold (1988) explain this phenomenon according to distinct signals from granulomatous inflammation that enhances proliferation of T lymphocytes and lymphokine gene expression. These enhancements promote IL-2 production, as there is a complex interplay between IL-2 and inflammatory signals during infection (Pipkin et al 2010). These data are in line with our data through the elevation of IL-2 in schistosomal infection and the higher significance value in schistosomal colonic carcinoma patients.…”

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

“…In fact, the earliest memory cell precursors are characterized by specific loss of CD25 expression several days before CD127 is re-expressed, but when CD122 and NKG2D levels are high (Ref. 23) and this study). Thus, memory differentiation involves a transition phase from IL-2 to IL-7 dependency, during which activated cells highly rely on IL-15/NKG2D signaling for their survival (Supplemental Fig.…”

“…If it primarily promotes T CM cell survival, NKG2D deficiency will only negatively impact memory cell numbers. OT-1 or Klrk1 D/D OT-1 cells were transferred into naive recipients, which were subsequently infected with mCMV-SIINFEKL and analyzed after 5 d. At this time point, low CD25 expression is associated with memory differentiation, whereas high CD25 expression defines cells with effector potential (23). Strikingly, NKG2D-deficient cells generated significantly fewer CD25 low memory precursors, whereas the number of CD25 high effectors was not affected (Fig.…”

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…Highly specialized regulatory T cells (Tregs) are dependent on IL-2 for survival and express large numbers of IL-2Ra, but they are unable to produce IL-2. These cells are thought to mediate active but selective immune suppression and are critical in the maintenance of self-tolerance (Rouse and Suvas 2004;Burchill et al 2007;Josefowicz and Rudensky 2009;Pipkin et al 2010;Kalia et al 2010). …”