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This information is current as Production Differentiation by Restricting Autocrine IL-2 T Cell + Ikaros Imposes a Barrier to CD 8
| Content Provider | Semantic Scholar |
|---|---|
| Author | O'Brien, Shaun Thomas, Rajan M. Wertheim, Gerald B. W. Zhang, Fuqin Shen, Hao Wells, Andrew |
| Copyright Year | 2014 |
| 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 transcrip-tional 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-g–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-g–producing effectors. Therefore, by repressing auto-crine 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. N aive T cell differentiation is a tightly regulated process, as aberrant activation can lead to immunopathology and disease. Naive CD4 + and CD8 + T cells differ in their requirements for differentiation, as the latter have higher cytotoxicity potential. Naive CD4 + T cells require TCR recognition of a cognate peptide in a class II MHC molecule and a costimulatory signal from CD28-B7 engagement. Upon receiving these two signals, CD4 + T cells can produce autocrine IL-2 and differentiate (1). In contrast, costimulation of naive CD8 + T cells through the TCR and CD28 does not result in efficient autocrine IL-2 production (2) and is not sufficient for differentiation into cytolytic effectors. In addition to TCR and CD28, CD8 + T cells require proinflammatory cytokines for their differentiation. For instance, IL-12, type I IFNs, and IL-21 have been characterized as key inflammatory cytokines that drive naive CD8 + T cells into full-fledged cytotoxic effectors (3). Typically, these cytokines are derived from dendritic cells or CD4 + T cells to help promote the appropriate effector immune … |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.jimmunol.org/content/jimmunol/192/11/5118.full.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
