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The transcription factor Zfp281 sustains CD4⁺ T lymphocyte activation through directly repressing Ctla-4 transcription.

ABSTRACT: The expression of coinhibitory receptors, such as CTLA-4, on effector T cells is a key mechanism for the negative regulation of T-cell activation. However, the transcriptional regulation of CTLA-4 is not well understood. Zfp281, a C2H2 zinc finger protein, is a negative regulator of pluripotency maintenance of embryonic stem cells. Nevertheless, the function of Zfp281 in differentiated cells has not been studied. We generated Zfp281 conditional knockout mice in which the function of the Zfp281 gene was conditionally disrupted by the Cd4^Cre transgene to study its impact on T cell function. Zfp281 had no effect on T-cell development, but CD4⁺ T cell activation and cytokine production were impaired due to diminished T-cell receptor signaling. Furthermore, Zfp281 deficiency inhibited in vivo T cell responses to Listeria monocytogenes infection. Using genome-wide expression profiling assays, we determined that Zfp281 repressed Ctla-4 expression by directly binding to GC-rich sites in its promoter, which inhibited the negative feedback of T cell activation. In line with this result, CTLA-4 blockade and shRNA knockdown partly rescued the reduced cytokine production caused by Zfp281 deficiency. These findings indicate that Zfp281 sustains CD4⁺ T lymphocyte activation by directly repressing Ctla-4 transcription.

SUBMITTER: Guo J

PROVIDER: S-EPMC7784856 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The transcription factor Zfp281 sustains CD4<sup>+</sup> T lymphocyte activation through directly repressing Ctla-4 transcription.

Guo Jing J Xue Zhonghui Z Ma Ruoyu R Yi Weiwei W Hui Zhaoyuan Z Guo Yixin Y Yao Yuxi Y Cao Wenqiang W Wang Jianli J Ju Zhenyu Z Lu Linrong L Wang Lie L

Cellular & molecular immunology 20190911 12

The expression of coinhibitory receptors, such as CTLA-4, on effector T cells is a key mechanism for the negative regulation of T-cell activation. However, the transcriptional regulation of CTLA-4 is not well understood. Zfp281, a C2H2 zinc finger protein, is a negative regulator of pluripotency maintenance of embryonic stem cells. Nevertheless, the function of Zfp281 in differentiated cells has not been studied. We generated Zfp281 conditional knockout mice in which the function of the Zfp281 g ...[more]

PMID: 31511645

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Project description:BackgroundThe protein kinase C theta (PKCθ) has an important and non-redundant function downstream of the antigen receptor and co-receptor complex in T lymphocytes. PKCθ is not only essential for activation of NF-κB, AP-1 and NFAT and subsequent interleukin-2 expression, but also critical for positive selection and development of regulatory T lymphocytes in the thymus. Several domains regulate its activity, such as a pseudosubstrate sequence mediating an auto-inhibitory intramolecular interaction, the tandem C1 domains binding diacylglycerol, and phosphorylation at conserved tyrosine, threonine as well as serine residues throughout the whole length of the protein. To address the importance of the variable domain V1 at the very N-terminus, which is encoded by exon 2, a mutated version of PKCθ was analyzed for its ability to stimulate T lymphocyte activation.MethodsT cell responses were analyzed with promoter luciferase reporter assays in Jurkat T cells transfected with PKCθ expression constructs. A mouse line expressing mutated instead of wild type PKCθ was analyzed in comparison to PKCθ-deficient and wild type mice for thymic development and T cell subsets by flow cytometry and T cell activation by quantitative RT-PCR, luminex analysis and flow cytometry.ResultsIn cell lines, the exon 2-replacing mutation impaired the transactivation of interleukin-2 expression by constitutively active mutant form of PKCθ. Moreover, analysis of a newly generated exon 2-mutant mouse line (PKCθ-E2mut) revealed that the N-terminal replacement mutation results in an hypomorph mutant of PKCθ combined with reduced PKCθ protein levels in CD4+ T lymphocytes. Thus, PKCθ-dependent functions in T lymphocytes were affected resulting in impaired thymic development of single positive T lymphocytes in vivo. In particular, there was diminished generation of regulatory T lymphocytes. Furthermore, early activation responses such as interleukin-2 expression of CD4+ T lymphocytes were significantly reduced even though cell viability was not affected. Thus, PKCθ-E2mut mice show a phenotype similar to conventional PKCθ-deficient mice.ConclusionTaken together, PKCθ-E2mut mice show a phenotype similar to conventional PKCθ-deficient mice. Both our in vitro T cell culture experiments and ex vivo analyses of a PKCθ-E2-mutant mouse line independently validate the importance of PKCθ downstream of the antigen-receptor complex for activation of CD4+ T lymphocytes.

Dataset Information

The transcription factor Zfp281 sustains CD4⁺ T lymphocyte activation through directly repressing Ctla-4 transcription.

Publications

The transcription factor Zfp281 sustains CD4<sup>+</sup> T lymphocyte activation through directly repressing Ctla-4 transcription.

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The transcription factor Zfp281 sustains CD4+ T lymphocyte activation through directly repressing Ctla-4 transcription.

Publications

The transcription factor Zfp281 sustains CD4<sup>+</sup> T lymphocyte activation through directly repressing Ctla-4 transcription.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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The transcription factor Zfp281 sustains CD4⁺ T lymphocyte activation through directly repressing Ctla-4 transcription.