Ikaros Imposes a Barrier to CD8+ T Cell Differentiation by Restricting Autocrine IL-2 Production

Authors:
Publisher website
Google Scholar
Abstract
Naive CD4+ T cells require signals from the TCR and CD28 to produce IL-2, expand, and differentiate. However, these same signals are not sufficient to induce autocrine IL-2 production by naive CD8+ T cells, which require cytokines provided by other cell types to drive their differentiation. The basis for failed autocrine IL-2 production by activated CD8+ cells is unclear. We find that Ikaros, a transcriptional repressor that silences IL-2 in anergic CD4+ T cells, also restricts autocrine IL-2 production by CD8+ T cells. We find that CD8+ T cell activation in vitro in the absence of exogenous cytokines and CD4 help leads to marked induction of Ikaros, a known repressor of the Il2 gene. Naive murine CD8 T cells haplo-insufficient for Ikzf1 failed to upregulate Ikaros, produced autocrine IL-2, and differentiated in an IL-2–dependent manner into IFN-γ–producing CTLs in response to TCR/CD28 stimulation alone. Furthermore, Ikzf1 haplo-insufficient CD8+ T cells were more effective at controlling Listeria infection and B16 melanoma growth in vivo, and they could provide help to neighboring, non-IL-2–producing cells to differentiate into IFN-γ–producing effectors. Therefore, by repressing autocrine IL-2 production, Ikaros ensures that naive CD8+ T cells remain dependent on licensing by APCs and CD4+ T cells, and it may therefore act as a cell-intrinsic safeguard against inappropriate CTL differentiation and immunopathology.

This publication has 70 references indexed in Scilit: