title: Mnk1 and 2 are dispensable for T cell development and activation but important for the pathogenesis of experimental autoimmune encephalomyelitis.
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 (Mnk1/2) promote cap-dependent translation by phosphorylating eIF4E at serine 209 (S209). Pharmacologic studies using inhibitors have suggested that Mnk1/2 have important roles in T cells. However, genetic evidence supporting such conclusions is lacking. Moreover, the signaling pathways that regulate Mnk1/2 in T cells remain unclear. We demonstrate that TCR engagement activates Mnk1/2 in primary T cells. Such activation is dependent on Ras-Erk1/2 signaling and is inhibited by diacylglycerol kinases α and ζ. Mnk1/2 double deficiency in mice abolishes TCR-induced eIF4E S209 phosphorylation, indicating their absolute requirement for eIF4E S209 phosphorylation. However, Mnk1/2 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 Mnk1/2 deficiency. Although Mnk1/2 deficiency causes decreased IL-17 and IFN-γ 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 Mnk1/2 has a minimal role in T cell development and activation but may regulate non-T cell lineages to control Th1 and Th17 differentiation in vivo.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Balachandra K
authors.initials: BK
authors.lastname: Gorentla
authors.forename: Sruti
authors.initials: S
authors.lastname: Krishna
authors.forename: Jinwook
authors.initials: J
authors.lastname: Shin
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Mari L
authors.initials: ML
authors.lastname: Shinohara
authors.forename: Jason M
authors.initials: JM
authors.lastname: Grayson
authors.forename: Rikiro
authors.initials: R
authors.lastname: Fukunaga
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
mesh_terms: D019264:Adoptive Transfer; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D038041:Lymphopoiesis / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D055611:Natural Killer T-Cells / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011687:Purines / Q000494:pharmacology; D012315:RNA Caps; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D000814:Aniline Compounds; C466997:CGP 57380; D039561:Eukaryotic Initiation Factor-4E; D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; C110366:OVA-8; D010446:Peptide Fragments; D011687:Purines; D012315:RNA Caps; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D010047:Ovalbumin; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; D017346:Protein Serine-Threonine Kinases