Dataset Information

IRF4 Modulates CD8+ T Cell Sensitivity to IL-2 Family Cytokines.

ABSTRACT: IFN regulatory factor 4 (IRF4) is a key transcription factor that promotes effector CD8+ T cell differentiation and expansion. The roles of IRF4 in regulating the CD8+ T cell response to cytokines have not been explored. In this article, we show that IL-2 and IL-15 signaling and STAT5 activation regulate IRF4 expression in CD8+ T cells. Gene-expression profile analysis has also revealed that IRF4 is required for expression of the receptors of IL-2 family cytokines CD122 and CD127. We found that IRF4 binds directly to CD122 and CD127 gene loci, indicating that it may directly promote CD122 and CD127 gene transcription. As a consequence, IRF4-deficient CD8+ T cells show diminished sensitivity to IL-2, IL-15, and IL-7 treatment in vitro. Furthermore, we found that IRF4-deficient CD8+ T cells had lower expression of CD122 and CD127 in vivo during influenza virus infection. These data suggest that IRF4 regulates the sensitivity of CD8+ T cells to IL-2 family cytokines, which correlates with the diminished effector and memory CD8+ T cell responses in IRF4-deficient CD8+ T cells.

SUBMITTER: Huang S

PROVIDER: S-EPMC5858712 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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IRF4 Modulates CD8+ T Cell Sensitivity to IL-2 Family Cytokines.

Huang Su S Shen Yingjia Y Pham Duy D Jiang Li L Wang Zheng Z Kaplan Mark H MH Zhang Guangjun G Sun Jie J

ImmunoHorizons 20170814 6

IFN regulatory factor 4 (IRF4) is a key transcription factor that promotes effector CD8+ T cell differentiation and expansion. The roles of IRF4 in regulating the CD8+ T cell response to cytokines have not been explored. In this article, we show that IL-2 and IL-15 signaling and STAT5 activation regulate IRF4 expression in CD8+ T cells. Gene-expression profile analysis has also revealed that IRF4 is required for expression of the receptors of IL-2 family cytokine ...[more]

PMID: 29564420

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Project description:Interleukin-10 (IL-10) family of cytokines includes a number of its viral homologs and eight cellular cytokines (IL-19, IL-20, IL-22, IL-24, IL-26, IL-28A, IL-28B, and IL-29). The latter three proteins are also known as IFN-?2, IFN-?3, and IFN-?1, and are recognized as type III (or ?) interferons. Most of the cellular homologs of IL-10 are monomeric in solution, whereas IL-10 and its viral homologs are intercalated dimers consisting of two helical bundle domains topologically similar to the monomeric members of the family. A classical four-helix bundle, a signature element of all helical cytokines, is always found as part of the domain of each member of the IL-10 family. The only crystal structures of these cytokine receptors that have been determined to date are for their extracellular domains (ECDs). Each ECD consists of two ?-sandwich domains connected in the middle by a linkage. Signal transduction occurs when a cytokine binds to its two appropriate receptor chains. IL-10 and its viral homologs use the same IL-10 receptor system, whereas the cellular homologs of IL-10 use their own receptors, which in some cases may overlap and be used in different pairwise combinations. The known structures of binary complexes allowed for marking of the receptor binding site, which always includes helix A, loop AB and helix F (IL-10 notations) on the side of a ligand, loops of the N-terminal and C-terminal domains directed toward the ligand, and the interdomain linkage of the ECD. An analysis of the published structures of both the binary and ternary complexes of all helical cytokines allowed for the generation of a model of the signaling complex of IL-10. The receptor binding site I of the high affinity receptor IL-10R1 is exactly the same as in the crystal structure of the binary IL-10/sIL-10R1 complex, whereas the receptor binding site II is located on the surface of the first and the third helices of the four-helix bundle. The receptor/receptor interface, or site III, is formed between the C-terminal domains of IL-10R1 and IL-10R2.

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IRF4 Modulates CD8+ T Cell Sensitivity to IL-2 Family Cytokines.

Publications

IRF4 Modulates CD8<sup>+</sup> T Cell Sensitivity to IL-2 Family Cytokines.

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