In:
The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 127.7-127.7
Abstract:
RNA binding proteins, such as HuR (ELAVL1), fine tune gene expression in activated T cells by interacting with their 3′ UTR AU-rich elements (AREs) via posttranscriptional gene regulation. IL-2 and many Th2 cytokine mRNAs contain 3′ UTR AREs. Thus, we hypothesized that HuR may play a critical role in CD4+ T cell differentiation by regulating IL-2 signaling pathways. We conditionally ablated HuR in CD4+ T cells (distal lck-Cre ROSA HuRfl/fl) to test this hypothesis. HuR KO T cells are able to develop and egress the thymus normally. However, these cells cannot shut off IL-2 production and display defects in Th2 differentiation and cytokine expression. Proliferation defects, decreased p-stat5, and reductions in CD25 and prdm-1 transcription were also observed in the HuR KO T cells. In the absence of HuR, Il2ra (CD25) mRNA recruitment to heavy polysomes is reduced, indicating that HuR plays a critical role in its translation. This suggests that HuR regulates T cell activation and IL-2 homeostasis by controlling CD25 expression. When activated under Th0 conditions, 97% of HuR KO cells expressed IL-2 on day 5 compared to HuR WT cells (50%). HuR KO cells also had large increases in steady state IL-2 mRNA (30-fold) and 7-fold increases in secreted IL-2 protein. Furthermore, HuR KO cells produced scant amounts of the Th2 cytokines at the protein level. These findings led us to investigate the fate of other T cell lineages when HuR is absent. When polarized to Treg, Th17, and Tfh lineages, HuR KO T cells showed reduced levels of the signature transcription factors Foxp3, RoRγt, and Bcl6, respectively, as compared to controls. Thus, we conclude that HuR plays an indispensable role in normal IL-2 homeostasis and CD4+ T cell differentiation.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.196.Supp.127.7
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2016
detail.hit.zdb_id:
1475085-5
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