Dataset Information

Identification of Casz1 as a Regulatory Protein Controlling T Helper Cell Differentiation, Inflammation, and Immunity.

ABSTRACT: While T helper (Th) cells play a crucial role in host defense, an imbalance in Th effector subsets due to dysregulation in their differentiation and expansion contribute to inflammatory disorders. Here, we show that Casz1, whose function is previously unknown in CD4⁺ T cells, coordinates Th differentiation in vitro and in vivo. Casz1 deficiency in CD4⁺ T cells lowers susceptibility to experimental autoimmune encephalomyelitis, consistent with the reduced frequency of Th17 cells, despite an increase in Th1 cells in mice. Loss of Casz1 in the context of mucosal Candida infection severely impairs Th17 and T_reg responses, and lowers the ability of the mice to clear the secondary infection. Importantly, in both the models, absence of Casz1 causes a significant diminution in IFN-γ⁺IL-17A⁺ double-positive inflammatory Th17 cells (Th1* cells) in tissues in vivo. Transcriptome analyses of CD4⁺ T cells lacking Casz1 show a signature consistent with defective Th17 differentiation. With regards to Th17 differentiation, Casz1 limits repressive histone marks and enables acquisition of permissive histone marks at Rorc, Il17a, Ahr, and Runx1 loci. Taken together, these data identify Casz1 as a new Th plasticity regulator having important clinical implications for autoimmune inflammation and mucosal immunity.

SUBMITTER: Bhaskaran N

PROVIDER: S-EPMC5808336 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Identification of Casz1 as a Regulatory Protein Controlling T Helper Cell Differentiation, Inflammation, and Immunity.

Bhaskaran Natarajan N Liu Zhihui Z Saravanamuthu Senthil S SS Yan Chunhua C Hu Ying Y Dong Lijin L Zelenka Peggy P Zheng Lixin L Bletsos Vassili V Harris Rachel R Harrington Brenna B Weinberg Aaron A Thiele Carol J CJ Ye Fengchun F Pandiyan Pushpa P

Frontiers in immunology 20180207

While T helper (Th) cells play a crucial role in host defense, an imbalance in Th effector subsets due to dysregulation in their differentiation and expansion contribute to inflammatory disorders. Here, we show that Casz1, whose function is previously unknown in CD4+ T cells, coordinates Th differentiation in vitro and in vivo. Casz1 deficiency in CD4+ T cells lowers susceptibility to experimental autoimmune encephalomyelitis, consistent with the reduced frequ ...[more]

PMID: 29467767

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Project description:During activation, the T cell transmembrane receptor CD6 becomes incorporated into the T cell immunological synapse where it can exert both co-stimulatory and co-inhibitory functions. Given the ability of CD6 to carry out opposing functions, this study sought to determine how CD6 regulates early T cell activation in response to viral infection. Infection of CD6-deficient mice with a neurotropic murine coronavirus resulted in greater activation and expansion of CD4 T cells in the draining lymph nodes. Further analysis demonstrated that there was also preferential differentiation of CD4 T cells into T follicular helper cells, resulting in accelerated germinal center responses and emergence of high-affinity virus-specific antibodies. Given that CD6 conversely supports CD4 T cell activation in many autoimmune models, we probed potential mechanisms of CD6-mediated suppression of CD4 T cell activation during viral infection. Analysis of CD6 binding proteins revealed that infection-induced upregulation of Ubash3a, a negative regulator of T cell receptor (TCR) signaling, was hindered in CD6-deficient lymph nodes. Consistent with greater T cell activation and reduced UBASH3a activity, the T cell receptor signal strength was intensified in CD6-deficient CD4 T cells. These results reveal a novel immunoregulatory role for CD6 in limiting CD4 T cell activation and deterring CD4 T follicular helper cell differentiation, thereby attenuating antiviral humoral immunity.ImportanceCD6 monoclonal blocking antibodies are being therapeutically administered to inhibit T cell activation in autoimmune disorders. However, the multifaceted nature of CD6 allows for multiple and even opposing functions under different circumstances of T cell activation. We therefore sought to characterize how CD6 regulates T cell activation in the context of viral infections using an in vivo murine coronavirus model. In contrast to its role in autoimmunity, but consistent with its function in the presence of superantigens, we found that CD6 deficiency enhances CD4 T cell activation and CD4 T cell help to germinal center-dependent antiviral humoral responses. Finally, we provide evidence that CD6 regulates transcription of its intracellular binding partner UBASH3a, which suppresses T cell receptor (TCR) signaling and consequently T cell activation. These findings highlight the context-dependent flexibility of CD6 in regulating in vivo adaptive immune responses, which may be targeted to enhance antiviral immunity.

Dataset Information

Identification of Casz1 as a Regulatory Protein Controlling T Helper Cell Differentiation, Inflammation, and Immunity.

Publications

Identification of Casz1 as a Regulatory Protein Controlling T Helper Cell Differentiation, Inflammation, and Immunity.

Similar Datasets

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