1. Mnkl and 2 Are Dispensable for T Cell Development and Activation but Important for the Pathogenesis of Experimental Autoimmune Encephalomyelitis.
- Author
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Gorentla, Balachandra K., Krishna, Sruti, Shin, Jinwook, Inoue, Makoto, Shinohara, Mari L., Grayson, Jason M., Fukunaga, Rikiro, and Zhong, Xiao-Ping
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T cells , *ENCEPHALOMYELITIS , *AUTOIMMUNE diseases , *GENETIC translation , *MESSENGER RNA , *MITOGEN-activated protein kinases - Abstract
T cell development and activation are usually accompanied by expansion and production of numerous proteins that require active translation. The eukaryotic translation initiation factor 4E (eIF4E) binds to the 5' cap structure of mRNA and is critical for cap-dependent translational initiation. It has been hypothesized that MAPK-interacting kinase 1 and 2 (Mnkl/2) promote cap-dependent translation by phosphorylating eIF4E at serine 209 (S209). Pharmacologic studies using inhibitors have suggested that Mnkl/2 have important roles in T cells. However, genetic evidence supporting such conclusions is lacking. Moreover, the signaling pathways that regulate Mnkl/2 in T cells remain unclear. We demonstrate that TCR engagement activates Mnkl/2 in primary T cells. Such activation is dependent on Ras-Erkl/2 signaling and is inhibited by diacylglycerol kinases α and ξ. Mnkl/2 double deficiency in mice abolishes TCR-induced eIF4E S209 phosphorylation, indicating their absolute requirement for eIF4E S209 phosphorylation. However, Mnkl/2 double deficiency does not affect the development of conventional αβ T cells, regulatory T cells, or NKT cells. Furthermore, T cell activation, in vivo primary and memory CD8 T cell responses to microbial infection, and NKT cell cytokine production were not obviously altered by Mnkl/2 deficiency. Although Mnkl/2 deficiency causes decreased IL-17 and IFN-ɣ production by CD4 T cells following immunization of mice with myelin oligodendrocyte glycoprotein peptide in complete Freund's adjuvant, correlating with milder experimental autoimmune encephalomyelitis scores, it does not affect Th cell differentiation in vitro. Together, these data suggest that Mnkl/2 has a minimal role in T cell development and activation but may regulate non-T cell lineages to control Thl and Thl7 differentiation in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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