Roquin Paralogs 1 and 2 Redundantly Repress the Icos and Ox40 Costimulator mRNAs and Control Follicular Helper T Cell Differentiation

被引：176

作者：

Vogel, Katharina U. ^{[1
]}

Edelmann, Stephanie L. ^{[1
]}

Jeltsch, Katharina M. ^{[1
]}

Bertossi, Arianna ^{[2
]}

Heger, Klaus ^{[2
]}

Heinz, Gitta A. ^{[1
]}

Zoeller, Jessica ^{[3
]}

Warth, Sebastian C. ^{[1
]}

Hoefig, Kai P. ^{[1
]}

Lohs, Claudia ^{[1
]}

Neff, Frauke ^{[4
]}

Kremmer, Elisabeth ^{[1
]}

Schick, Joel ^{[5
]}

Repsilber, Dirk ^{[7
]}

Geerlof, Arie ^{[6
]}

Blum, Helmut ^{[8
]}

Wurst, Wolfgang ^{[5
,9
,10
,11
]}

Heikenwaelder, Mathias ^{[3
]}

Schmidt-Supprian, Marc ^{[2
]}

Heissmeyer, Vigo ^{[1
,12
]}

机构：

[1] Helmholtz Zentrum Munchen, Inst Mol Immunol, D-81377 Munich, Germany

[2] Max Planck Inst Biochem, D-82152 Martinsried, Germany

[3] Tech Univ Munich, Inst Virol, Helmholtz Zentrum Munchen, D-81675 Munich, Germany

[4] Helmholtz Zentrum Munchen, Inst Pathol, D-85764 Neuherberg, Germany

[5] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany

[6] Helmholtz Zentrum Munchen, Inst Biol Struct, D-85764 Neuherberg, Germany

[7] Leibniz Inst Farm Anim Biol, D-18196 Dummerstorf, Germany

[8] Univ Munich, Gene Ctr, Lab Funct Genome Anal, D-81377 Munich, Germany

[9] Max Planck Inst Psychiat, D-80804 Munich, Germany

[10] Tech Univ Munich, Lehrstuhl Entwicklungsgenet, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany

[11] Deutsch Zentrum Neurodegenerat Erkrankungen eV DZ, D-80336 Munich, Germany

[12] Univ Munich, Inst Immunol, D-80336 Munich, Germany

来源：

IMMUNITY | 2013年 / 38卷 / 04期

关键词：

TRANSCRIPTION FACTOR IRF4; B-CELLS; EXPRESSION; AUTOIMMUNITY; LEADS; BCL6; ACCUMULATION; GENERATION; REGULATORS; FAMILY;

D O I：

10.1016/j.immuni.2012.12.004

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：655 / 668

页数：14

共 46 条

[1] In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines [J].

Ansel, KM ;

McHeyzer-Williams, LJ ;

Ngo, VN ;

McHeyzer-Williams, MG ;

Cyster, JG .

JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (08) :1123-1134

[2] The ROQUIN family of proteins localizes to stress granules via the ROQ domain and binds target mRNAs [J].

Athanasopoulos, Vicki ;

Barker, Andrew ;

Yu, Di ;

Tan, Andy H-M. ;

Srivastava, Monika ;

Contreras, Nelida ;

Wang, Jianbin ;

Lam, Kong-Peng ;

Brown, Simon H. J. ;

Goodnow, Christopher C. ;

Dixon, Nicholas E. ;

Leedman, Peter J. ;

Saint, Robert ;

Vinuesa, Carola G. .

FEBS JOURNAL, 2010, 277 (09) :2109-2127

[3] Generation and activation of multiple dimeric transcription factors within the NF-κB signaling system [J].

Basak, Soumen ;

Shih, Vincent Feng-Sheng ;

Hoffmann, Alexander .

MOLECULAR AND CELLULAR BIOLOGY, 2008, 28 (10) :3139-3150

[4] Cutting Edge: Distinct Waves of BCL6 Expression during T Follicular Helper Cell Development [J].

Baumjohann, Dirk ;

Okada, Takaharu ;

Ansel, K. Mark .

JOURNAL OF IMMUNOLOGY, 2011, 187 (05) :2089-2092

[5] The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells [J].

Bauquet, Aurelie T. ;

Jin, Hulin ;

Paterson, Alison M. ;

Mitsdoerffer, Meike ;

Ho, I-Cheng ;

Sharpe, Arlene H. ;

Kuchroo, Vijay K. .

NATURE IMMUNOLOGY, 2009, 10 (02) :167-175

[6] Loss of Roquin induces early death and immune deregulation but not autoimmunity [J].

Bertossi, Arianna ;

Aichinger, Martin ;

Sansonetti, Paola ;

Lech, Maciej ;

Neff, Frauke ;

Pal, Martin ;

Wunderlich, F. Thomas ;

Anders, Hans-Joachim ;

Klein, Ludger ;

Schmidt-Supprian, Marc .

JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (09) :1749-1756

[7] Batf coordinates multiple aspects of B and T cell function required for normal antibody responses [J].

Betz, Briana C. ;

Jordan-Williams, Kimberly L. ;

Wang, Chuanwu ;

Kang, Seung Goo ;

Liao, Juan ;

Logan, Michael R. ;

Kim, Chang H. ;

Taparowsky, Elizabeth J. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2010, 207 (05) :933-942

[8] Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation [J].

Bollig, Nadine ;

Bruestle, Anne ;

Kellner, Kerstin ;

Ackermann, Waltraud ;

Abass, Elfadil ;

Raifer, Hartmann ;

Camara, Baerbel ;

Brendel, Cornelia ;

Giel, Gavin ;

Bothur, Evita ;

Huber, Magdalena ;

Paul, Christoph ;

Elli, Alexandra ;

Kroczek, Richard A. ;

Nurieva, Roza ;

Dong, Chen ;

Jacob, Ralf ;

Mak, Tak W. ;

Lohoff, Michael .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (22) :8664-8669

[9]

Brocker T, 1999, EUR J IMMUNOL, V29, P1610, DOI 10.1002/(SICI)1521-4141(199905)29:05<1610::AID-IMMU1610>3.0.CO

[10]

2-8

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