A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity


Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.

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Figure 1: Lupus-like pathology in sanroque mice.
Figure 2: Intrinsic T cell abnormalities.
Figure 3: Dysregulated T cell responses to TCR stimuli.
Figure 4: Increased germinal centres and follicular helper T cells.
Figure 5: Missense mutation in a conserved gene of previously unknown function.
Figure 6: Expression and function of Roquin protein.


  1. 1

    Wakeland, E., Liu, K., Graham, R. & Behrens, T. Delineating the genetic basis of systemic lupus erythematosus. Immunity 15, 397–408 (2001)

  2. 2

    Mills, D. M. & Cambier, J. C. B lymphocyte activation during cognate interactions with CD4 + T lymphocytes: molecular dynamics and immunologic consequences. Semin. Immunol. 15, 325–329 (2003)

  3. 3

    Tafuri, A. et al. ICOS is essential for effective T-helper-cell responses. Nature 409, 105–109 (2001)

  4. 4

    McAdam, A. J. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102–105 (2001)

  5. 5

    Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–101 (2001)

  6. 6

    Dong, C., Temann, U. A. & Flavell, R. A. Cutting edge: critical role of inducible costimulator in germinal center reactions. J. Immunol. 166, 3659–3662 (2001)

  7. 7

    Mak, T. W. et al. Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nature Immunol. 4, 765–772 (2003)

  8. 8

    Wong, S. C., Oh, E., Ng, C. H. & Lam, K. P. Impaired germinal center formation and recall T-cell-dependent immune responses in mice lacking the costimulatory ligand B7–H2. Blood 102, 1381–1388 (2003)

  9. 9

    Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57–63 (2000)

  10. 10

    Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002)

  11. 11

    MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994)

  12. 12

    Walker, L. S., Gulbranson-Judge, A., Flynn, S., Brocker, T. & Lane, P. J. Co-stimulation and selection for T-cell help for germinal centres: the role of CD28 and OX40. Immunol. Today 21, 333–337 (2000)

  13. 13

    Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999)

  14. 14

    Lohning, M. et al. Expression of ICOS in vivo defines CD4 + effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J. Exp. Med. 197, 181–193 (2003)

  15. 15

    Moser, B., Schaerli, P. & Loetscher, P. CXCR5+ T cells: follicular homing takes center stage in T-helper-cell responses. Trends Immunol. 23, 250–254 (2002)

  16. 16

    Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173, 68–78 (2004)

  17. 17

    Kim, C. H. et al. Unique gene expression program of human germinal center T helper cells. Blood 104, 1952–1960 (2004)

  18. 18

    Grimbacher, B. et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nature Immunol. 4, 261–268 (2003)

  19. 19

    Toellner, K. M. et al. T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching. J. Exp. Med. 187, 1193–1204 (1998)

  20. 20

    Jun, J. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003)

  21. 21

    Akkaraju, S. et al. A range of CD4 T cell tolerance: partial inactivation to organ-specific antigen allows nondestructive thyroiditis or insulitis. Immunity 7, 255–271 (1997)

  22. 22

    Lesage, S. et al. Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes. J. Exp. Med. 196, 1175–1188 (2002)

  23. 23

    Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. Aire regulates negative selection of organ-specific T cells. Nature Immunol. 4, 350–354 (2003)

  24. 24

    Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002)

  25. 25

    Scherer, M. T., Ignatowicz, L., Pullen, A., Kappler, J. & Marrack, P. The use of mammary tumor virus (Mtv)-negative and single-Mtv mice to evaluate the effects of endogenous viral superantigens on the T cell repertoire. J. Exp. Med. 182, 1493–1504 (1995)

  26. 26

    Chiang, Y. et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216–220 (2000)

  27. 27

    Jeon, M. S. et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21, 167–177 (2004)

  28. 28

    Peng, S. L., Gerth, A. J., Ranger, A. M. & Glimcher, L. NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity 14, 13–20 (2001)

  29. 29

    Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4 + CD25 + T regulatory cells. Nature Immunol. 4, 337–342 (2003)

  30. 30

    Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells. Nature Immunol. 4, 330–336 (2003)

  31. 31

    Ozaki, K. et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173, 5361–5371 (2004)

  32. 32

    Yoshinaga, S. K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 (1999)

  33. 33

    Blackshear, P. J. Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover. Biochem. Soc. Trans. 30, 945–952 (2002)

  34. 34

    Barabino, S. M., Ohnacker, M. & Keller, W. Distinct roles of two Yth1p domains in 3′-end cleavage and polyadenylation of yeast pre-mRNAs. EMBO J. 19, 3778–3787 (2000)

  35. 35

    Hudson, B., Martinez-Yamout, M., Dyson, H. & Wright, P. Recognition of the mRNA AU-rich element by the zinc finger domain of TIS11d. Nature Struct. Mol. Biol. 11, 257–264 (2004)

  36. 36

    Morking, P. A. et al. TcZFP1: a CCCH zinc finger protein of Trypanosoma cruzi that binds poly-C oligoribonucleotides in vitro. Biochem. Biophys. Res. Commun. 319, 169–177 (2004)

  37. 37

    Anderson, P. & Kedersha, N. Stressful initiations. J. Cell Sci. 115, 3227–3234 (2002)

  38. 38

    Iwai, H. et al. Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J. Immunol. 171, 2848–2854 (2003)

  39. 39

    Hutloff, A. et al. Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. Arthritis Rheum. 50, 3211–3220 (2004)

  40. 40

    Greve, B. et al. The diabetes susceptibility locus Idd5.1 on mouse chromosome 1 regulates ICOS expression and modulates murine experimental autoimmune encephalomyelitis. J. Immunol. 173, 157–163 (2004)

  41. 41

    King, C., Ilic, A., Koelsch, K. & Sarvetnick, N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117, 265–277 (2004)

  42. 42

    Kearney, E. R., Pape, K. A., Loh, D. Y. & Jenkins, M. K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327–339 (1994)

  43. 43

    Fillatreau, S. & Gray, D. T cell accumulation in B cell follicles is regulated by dendritic cells and is independent of B cell activation. J. Exp. Med. 197, 195–206 (2003)

  44. 44

    Brocker, T. et al. CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles. Eur. J. Immunol. 29, 1610–1616 (1999)

  45. 45

    Zheng, N., Wang, P., Jeffrey, P. D. & Pavletich, N. P. Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell 102, 533–539 (2000)

  46. 46

    Zheng, N. et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002)

  47. 47

    Wickens, M. & Goldstrohm, A. A place to die, a place to sleep. Science 300, 753–755 (2003)

  48. 48

    Crotty, S., Kersh, E. N., Cannons, J., Schwartzberg, P. L. & Ahmed, R. SAP is required for generating long-term humoral immunity. Nature 421, 282–287 (2003)

  49. 49

    Okamoto, S. et al. Expression of the SH2D1A gene is regulated by a combination of transcriptional and post-transcriptional mechanisms. Eur. J. Immunol. 34, 3176–3186 (2004)

  50. 50

    Laroia, G., Cuesta, R., Brewer, G. & Schneider, R. J. Control of mRNA decay by heat shock–ubiquitin–proteasome pathway. Science 284, 499–502 (1999)

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We thank the staff of the Australian Phenomics Facility for care, breeding and phenotyping of mice; A. Prins for histology; D. Webb for help with cytokine ELISAs; E. Kucharska for help with immunizations; and A. Murtagh and D. Buckle for help with sequencing. The work was supported by grants from the Wellcome Trust (UK), the Juvenile Diabetes Research Foundation, the National Health and Medical Research Council, and the National Institutes of Health. C.G.V. was the recipient of a Wellcome Trust International Prize Travelling Fellowship.

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Correspondence to Carola G. Vinuesa or Christopher C. Goodnow.

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Competing interests

The mouse Roquin sequence has been deposited in GenBank under accession number AY948287. The gene symbols assigned by the mouse and human genome nomenclature committees are Rc3h1 and RC3H1, respectively. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures S1-S12

This file contains 12 Supplementary Figures that provide detailed characterization of the incidence, female:male bias and gene dose effects of the sanroque phenotype including ANAs, Ig titres, glomerulonephritis, flow cytometric analysis of all lymphoid compartments, immunohistology of splenic germinal centres, response to immunization and known tolerance pathways. Mapping and genotyping details of the sanroque mutation and Roquin mRNA expression are also provided, together with the full Roquin preotein sequence and phylogenetic conservation. (PDF 921 kb)

Supplementary Figures Legends

This file contains a brief description for each of the 12 Supplementary Figures. (DOC 49 kb)

Supplementary Methods

Details of the Supplementary Methods used for Flow cytometry, CFSE labelling, and immunohistology. (DOC 25 kb)

Supplementary Data

This file contains the microarray data referred to in the paper in MIAME-compliant format and a completed MIAME checklist. (XLS 14340 kb)

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Vinuesa, C., Cook, M., Angelucci, C. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005). https://doi.org/10.1038/nature03555

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