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

By M. Pipkin, J. Sacks, Fernando Cruz-Guilloty, M. Lichtenheld, M. Bevan, Anjana Rao. Immunity, 2010

796 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/edbbf7d6dfcd5033c8b7272055e0bb090b4bae0b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Jian-Xin Lin
2. W. Liao
3. M. Bevan
4. W. Leonard
5. Nu Zhang
6. Rafi Ahmed
7. Shane Crotty
8. T. Malek

Citations in the corpus

• IL-2 Family Cytokines: New Insights into the Complex Roles of IL-2 as a Broad Regulator of T helper Cell Differentiation (2011, background): “cells (Treg cells) to eliminate autoreactive T cells and promote self-tolerance [23], whereas IL-2 also promotes the differentiation of CD8 T cells into effector and memory cytolytic T lymphocytes (CTL) upon antigen stimulation [24 ,25 ,26].”
• Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy (2013, positive): “IL-2 via STAT5 induces BLIMP1, which suppresses Tfh differentiation and germinal center formation (Ballesteros-Tato et al., 2012; Johnston et al., 2012); IL-2 also inhibits BCL6 in Th1 cells, which suppresses a Tfh-like gene profile (Oestreich et al., 2012).”
• The transcription factor NFAT promotes exhaustion of activated CD8+ T cells (2015, positive): “When differentiated into ‘‘memory’’ CTLs (Pipkin et al., 2010) and restimulated with PMA and ionomycin in vitro, NFAT1,2 double-deficient CD8+ T cells showed clearly decreased induction of the effector cytokines IL-2 and IFN-g compared toWT or singly NFAT1- or NFAT2-deficient CD8+ T cells (Figure 5A”
• CD8+ T Cells: Foot Soldiers of the Immune System (2011, positive): “Il2ra (cid:1) / (cid:1) CD8 + effector T cells are defective in ex vivo killing, correlated with the decreased expression of granzymeB and perforin (Pipkin et al., 2010).”
• Bcl6 dependent T follicular helper cell differentiation diverges from effector cell differentiation during priming and depends on the gene Icos (2011, neutral): “IL-21 and IL-6 are critical for different aspects B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.”
• Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. (2016, background): “Although IL2 promotes effector differentiation and glycolysis in CD8+ T cells (Finlay et al., 2012; Liao et al., 2013; Pipkin et al., 2010), IL7 and IL15 have been implicated in the maintenance of memory T cells and increased mitochondrial biogenesis (Ku et al., 2000; Schluns and Lefrançois, 2003;…”
• Interleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity (2010, positive): “…and Bcl-6, which readily support an effector differentiation program leading to increased expression of granzyme B and perforin and the inability toproduce IL-2, the latterbecauseofdirect repression by Blimp-1 (Intlekofer et al., 2005; Joshi et al., 2007;Martins et al., 2008; Pipkin et al., 2010).”
• Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. (2010, background): “An accompanying article by Pipkin et al. (2010) in this issue of Immunity demonstrates that enhanced expression of perforin by highdose IL-2 is associated with Stat5 and Eomesodermin recruitment to the Prf1 locus.”