The RNA binding protein HuR is required for antigen-mediated activation and proliferation of CD4+T cells
| Autor: | Jason S Ellis, Tiffany Taylor, Ulus Atasoy |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 202:186.13-186.13 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The RNA binding protein HuR directs helper T cell fate decisions by interacting with 3′ AU-rich elements within the untranslated region of multiple target mRNAs, leading to increased stability and transport to the heavy polysomes. We hypothesized that HuR plays a key role in antigen-induced T cell activation and expansion. HuR was conditionally ablated late during T cell development, immediately before thymic egress (distal Lck-Cre ROSA HuRfl/fl mouse). Upon activation in vitro, HuR KO T cells had significant reductions in Th2 cytokine production (IL-4, IL-5, and IL-13) compared to control cells and greatly increased IL-2. There was no difference in IFNgproduction between HuR KO and controls. Reductions in Gata-3, IL-4 and IL-2Ra (CD25) nascent transcription were also observed. An OVA challenge model of airway inflammation was used to ascertain the effects of HuR KO in vivo. While only half of CD4+T cells in HuR KO mice lack HuR, there was a lack of Th2 responses and these mice had complete amelioration of lung inflammation. OVA challenged HuR KO mice also had significantly reduced BAL IL-13. In parallel, mice were immunized with either OVA or KLH, boosted 10 days later, and antigen specific proliferative responses measured in vitro to investigate antigen-specific T cell responses in the absence of HuR. HuR KO T cells had profound proliferation defects compared to controls, and CD3/CD28 stimulation only partially restored proliferation defects. HuR KO T cells had reductions in STAT5/STAT6 signaling, pathways which are key for Th2 differentiation and function. We conclude HuR plays an indispensable role in regulating antigen-specific activation and proliferation in CD4+T cells, as well as controlling IL-2 homeostasis. |
| Databáze: | OpenAIRE |
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