Treg-specific ablation of HuR results in systemic autoimmunity associated with decreased TLR4 activation and IL-1β production
| Autor: | Ulus Atasoy, Fatemeh Fattahi, Jason S Ellis, Sarah Socha, Kristin Bahleda |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 208:44.11-44.11 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The RNA-binding protein HuR (Elavl1) plays a critical role in T cell activation and function by regulating the stability and transport of its mRNA targets. To study the role of HuR in regulatory T cell (Treg) development and function, we generated the Foxp3YFP-Cre HuRfl/fl mouse in which HuR is selectively deleted in CD4+Foxp3+ cells, a lineage with crucial roles in self-tolerance and immune homeostasis. Foxp3+ Treg-specific HuR deletion results in abnormal phenotypic features (scurfy-like mice, hair loss, stippled/banded tails, significant failure to thrive, splenomegaly and multi-organ inflammation, including lung and lymphoid organs), likely the result of reduced Treg function, a phenotype similar to human IPEX syndrome (an autoimmune disorder). Unexpectedly, our RNAseq data showed reduced levels of TLR4, IL-1β, IL-18 and NLRP3 mRNA expression in HuR deficient Tregs (Foxp3YFP-Cre HuRfl/fl). In control WT mice, in vitro LPS treatment of Tregs induced increased expression of TLR4 and IL-1β production, associated with increased nucleocytoplasmic shuttling of HuR. In contrast, the expression of TLR4 and IL-1β was significantly decreased in Tregs from Foxp3YFP-Cre HuRfl/fl mice. Homozygous Foxp3YFP-Cre HuRfl/fl mice had statistically significant reductions in Treg numbers and increased frequency of activated effector T cells. We were also able to detect IL-1β secretion from WT Tregs in vitro following LPS treatment, which was amplified by the addition of DAMP agonists (e.g., ATP or Nigericin). In contrast, HuR KO Tregs had decreases in IL-1β secretion. Together, our data show that HuR is critical for normal CD4+Foxp3+ regulatory T cell function. Supported by grants from NIH (R01 AI080870 and R21 AI079341). |
| Databáze: | OpenAIRE |
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