title: Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation.
abstract: The Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4(+) T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form.
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Marchioninistrasse 25, Munich, Germany.
authors.forename: Katharina U
authors.initials: KU
authors.lastname: Vogel
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Edelmann
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Jeltsch
authors.forename: Arianna
authors.initials: A
authors.lastname: Bertossi
authors.forename: Klaus
authors.initials: K
authors.lastname: Heger
authors.forename: Gitta A
authors.initials: GA
authors.lastname: Heinz
authors.forename: Jessica
authors.initials: J
authors.lastname: Zöller
authors.forename: Sebastian C
authors.initials: SC
authors.lastname: Warth
authors.forename: Kai P
authors.initials: KP
authors.lastname: Hoefig
authors.forename: Claudia
authors.initials: C
authors.lastname: Lohs
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Joel
authors.initials: J
authors.lastname: Schick
authors.forename: Dirk
authors.initials: D
authors.lastname: Repsilber
authors.forename: Arie
authors.initials: A
authors.lastname: Geerlof
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwälder
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.forename: Vigo
authors.initials: V
authors.lastname: Heissmeyer
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D012333:RNA, Messenger; D053262:Receptors, OX40; D012097:Repressor Proteins; C582114:roquin-2 protein, mouse; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases