TY - JOUR
T1 - Roquin paralogs 1 and 2 redundantly repress the icos and ox40 costimulator mrnas and control follicular helper t cell differentiation
AU - Vogel, Katharina U.
AU - Edelmann, Stephanie L.
AU - Jeltsch, Katharina M.
AU - Bertossi, Arianna
AU - Heger, Klaus
AU - Heinz, Gitta A.
AU - Zöller, Jessica
AU - Warth, Sebastian C.
AU - Hoefig, Kai P.
AU - Lohs, Claudia
AU - Neff, Frauke
AU - Kremmer, Elisabeth
AU - Schick, Joel
AU - Repsilber, Dirk
AU - Geerlof, Arie
AU - Blum, Helmut
AU - Wurst, Wolfgang
AU - Heikenwälder, Mathias
AU - Schmidt-Supprian, Marc
AU - Heissmeyer, Vigo
N1 - Funding Information:
We would like to thank C. Wolf for expert technical assistance, C. Vahl for help with cell sorting, and R. Kroczek (Robert Koch Institute, Berlin, Germany) for Icos −/− mice. The PBS57-loaded CD1d tetramer was obtained through the National Institutes of Health Tetramer Facility. This work was supported by an ERC grant to V.H., the SFB1054 (TP-A03 to V.H.), a grant from the Thyssen foundation to V.H. and M.S.-S., a DFG Emmy Noether grant to M.S.-S., and by a grant of the FP7 program of the European Commission (EU) EUCOMMTOOLS (HEALTH-F4-2010-261492) to W.W. G.A.H and K.H. were supported by fellowships from Boehringer Ingelheim.
PY - 2013/4/18
Y1 - 2013/4/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84876781274&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2012.12.004
DO - 10.1016/j.immuni.2012.12.004
M3 - Article
C2 - 23583643
AN - SCOPUS:84876781274
SN - 1074-7613
VL - 38
SP - 655
EP - 668
JO - Immunity
JF - Immunity
IS - 4
ER -