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Siglec-G is a B1 cell–inhibitory receptor that controls expansion and calcium signaling of the B1 cell population

Nature Immunology volume 8, pages 695–704 (2007)Cite this article

Abstract

B1 cells are an important cell population for the production of natural antibodies and for antibacterial immunoglobulin responses. Here we identified the mouse protein Siglec-G as a B1 cell inhibitory receptor. Siglec-G was expressed in a B cell–restricted way, with large amounts present in B1 cells. When overexpressed, Siglec-G inhibited B cell receptor–mediated calcium signaling. Siglec-G-deficient mice had massive expansion of the B1a cell population, which began early in development and was B cell intrinsic. Siglec-G-deficient mice had higher titers of natural IgM antibodies but not a higher penetrance of IgG autoantibodies. Siglec-G-deficient B1 cells showed a strongly enhanced calcium signaling. Our results demonstrate that Siglec-G-dependent negative regulation exists in B1 cells, which may explain the naturally muted signaling response of B1 cells.

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Figure 1: Siglec-G is specifically expressed in B cells and inhibits anti-IgM-mediated calcium responses.
Figure 2: Expansion of B1a cell population in Siglecg−/− mice.
Figure 3: The B1a cell population expansion in Siglecg−/− mice is cell autonomous, occurs early after birth and can be explained by lower cellular turnover.
Figure 4: Enhanced calcium responses in B1a cells from Siglecg−/− mice.
Figure 5: Higher IgM titers in Siglecg−/− mice.
Figure 6: Immune responses of Siglecg−/− and wild-type mice.

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References

  1. Berland, R. & Wortis, H.H. Origins and functions of B-1 cells with notes on the role of CD5. Annu. Rev. Immunol. 20, 253–300 (2002).

    Article  CAS  Google Scholar 

  2. Martin, F. & Kearney, J.F. Marginal-zone B cells. Nat. Rev. Immunol. 2, 323–335 (2002).

    Article  CAS  Google Scholar 

  3. Haas, K.M., Poe, J.C., Steeber, D.A. & Tedder, T.F. B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity 23, 7–18 (2005).

    Article  CAS  Google Scholar 

  4. Alugupalli, K.R. et al. B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity 21, 379–390 (2004).

    Article  CAS  Google Scholar 

  5. Ha, S.A. et al. Regulation of B1 cell migration by signals through Toll-like receptors. J. Exp. Med. 203, 2541–2550 (2006).

    Article  CAS  Google Scholar 

  6. Herzenberg, L.A. B-1 cells: the lineage question revisited. Immunol. Rev. 175, 9–22 (2000).

    Article  CAS  Google Scholar 

  7. Montecino-Rodriguez, E., Leathers, H. & Dorshkind, K. Identification of a B-1 B cell-specified progenitor. Nat. Immunol. 7, 293–301 (2006).

    Article  CAS  Google Scholar 

  8. Cong, Y.Z., Rabin, E. & Wortis, H.H. Treatment of murine CD5- B cells with anti-Ig, but not LPS, induces surface CD5: two B-cell activation pathways. Int. Immunol. 3, 467–476 (1991).

    Article  CAS  Google Scholar 

  9. Lam, K.P. & Rajewsky, K. B cell antigen receptor specificity and surface density together determine B-1 versus B-2 cell development. J. Exp. Med. 190, 471–477 (1999).

    Article  CAS  Google Scholar 

  10. Sidman, C.L., Shultz, L.D., Hardy, R.R., Hayakawa, K. & Herzenberg, L.A. Production of immunoglobulin isotypes by Ly-1+ B cells in viable motheaten and normal mice. Science 232, 1423–1425 (1986).

    Article  CAS  Google Scholar 

  11. Pan, C., Baumgarth, N. & Parnes, J.R. CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation. Immunity 11, 495–506 (1999).

    Article  CAS  Google Scholar 

  12. Otipoby, K.L. et al. CD22 regulates thymus-independent responses and the lifespan of B cells. Nature 384, 634–637 (1996).

    Article  CAS  Google Scholar 

  13. Nitschke, L., Carsetti, R., Ocker, B., Kohler, G. & Lamers, M.C. CD22 is a negative regulator of B-cell receptor signalling. Curr. Biol. 7, 133–143 (1997).

    Article  CAS  Google Scholar 

  14. O'Keefe, T.L., Williams, G.T., Davies, S.L. & Neuberger, M.S. Hyperresponsive B cells in CD22-deficient mice. Science 274, 798–801 (1996).

    Article  CAS  Google Scholar 

  15. Sato, S. et al. CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice. Immunity 5, 551–562 (1996).

    Article  CAS  Google Scholar 

  16. Sen, G., Bikah, G., Venkataraman, C. & Bondada, S. Negative regulation of antigen receptor-mediated signaling by constitutive association of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells. Eur. J. Immunol. 29, 3319–3328 (1999).

    Article  CAS  Google Scholar 

  17. Bikah, G., Carey, J., Ciallella, J.R., Tarakhovsky, A. & Bondada, S. CD5-mediated negative regulation of antigen receptor-induced growth signals in B-1 B cells. Science 274, 1906–1909 (1996).

    Article  CAS  Google Scholar 

  18. Murakami, M., Yoshioka, H., Shirai, T., Tsubata, T. & Honjo, T. Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells. Int. Immunol. 7, 877–882 (1995).

    Article  CAS  Google Scholar 

  19. Steinberg, B.J., Smathers, P.A., Frederiksen, K. & Steinberg, A.D. Ability of the xid gene to prevent autoimmunity in (NZB × NZW)F1 mice during the course of their natural history, after polyclonal stimulation, or following immunization with DNA. J. Clin. Invest. 70, 587–597 (1982).

    Article  CAS  Google Scholar 

  20. Crocker, P.R., Paulson, J.C. & Varki, A. Siglecs and their roles in the immune system. Nat. Rev. Immunol. 7, 255–266 (2007).

    Article  CAS  Google Scholar 

  21. Angata, T., Margulies, E.H., Green, E.D. & Varki, A. Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms. Proc. Natl. Acad. Sci. USA 101, 13251–13256 (2004).

    Article  CAS  Google Scholar 

  22. Angata, T. Molecular diversity and evolution of the Siglec family of cell-surface lectins. Mol. Divers. 10, 555–566 (2006).

    Article  CAS  Google Scholar 

  23. Noben-Trauth, N., Kohler, G., Burki, K. & Ledermann, B. Efficient targeting of the IL-4 gene in a BALB/c embryonic stem cell line. Transgenic Res. 5, 487–491 (1996).

    Article  CAS  Google Scholar 

  24. Martin, F. & Kearney, J.F. B1 cells: similarities and differences with other B cell subsets. Curr. Opin. Immunol. 13, 195–201 (2001).

    Article  CAS  Google Scholar 

  25. Oetke, C., Kraal, G. & Crocker, P.R. The antigen recognized by MOMA-I is sialoadhesin. Immunol. Lett. 106, 96–98 (2006).

    Article  CAS  Google Scholar 

  26. Angata, T., Hingorani, R., Varki, N.M. & Varki, A. Cloning and characterization of a novel mouse Siglec, mSiglec-F: differential evolution of the mouse and human (CD33) Siglec-3-related gene clusters. J. Biol. Chem. 276, 45128–45136 (2001).

    Article  CAS  Google Scholar 

  27. Munday, J. et al. Identification, characterization and leucocyte expression of Siglec-10, a novel human sialic acid-binding receptor. Biochem. J. 355, 489–497 (2001).

    Article  CAS  Google Scholar 

  28. Whitney, G. et al. A new siglec family member, siglec-10, is expressed in cells of the immune system and has signaling properties similar to CD33. Eur. J. Biochem. 268, 6083–6096 (2001).

    Article  CAS  Google Scholar 

  29. Li, N. et al. Cloning and characterization of Siglec-10, a novel sialic acid binding member of the Ig superfamily, from human dendritic cells. J. Biol. Chem. 276, 28106–28112 (2001).

    Article  CAS  Google Scholar 

  30. Su, A.I. et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl. Acad. Sci. USA 101, 6062–6067 (2004).

    Article  CAS  Google Scholar 

  31. Forster, I., Muller, W., Schittek, B. & Rajewsky, K. Generation of long-lived B cells in germ-free mice. Eur. J. Immunol. 21, 1779–1782 (1991).

    Article  CAS  Google Scholar 

  32. Lentz, V.M., Hayes, C.E. & Cancro, M.P. Bcmd decreases the life span of B-2 but not B-1 cells in A/WySnJ mice. J. Immunol. 160, 3743–3747 (1998).

    CAS  PubMed  Google Scholar 

  33. Wardemann, H., Boehm, T., Dear, N. & Carsetti, R. B-1a B cells that link the innate and adaptive immune responses are lacking in the absence of the spleen. J. Exp. Med. 195, 771–780 (2002).

    Article  CAS  Google Scholar 

  34. Pao, L. et al. B cell-specific SHP1 deletion promotes B1a cell development and causes systemic autoimmunity. Immunity (in the press).

  35. Lajaunias, F. et al. Differentially regulated expression and function of CD22 in activated B- 1 and B-2 lymphocytes. J. Immunol. 168, 6078–6083 (2002).

    Article  CAS  Google Scholar 

  36. Kelm, S., Gerlach, J., Brossmer, R., Danzer, C.P. & Nitschke, L. The ligand-binding domain of CD22 is needed for inhibition of the B cell receptor signal, as demonstrated by a novel human CD22-specific inhibitor compound. J. Exp. Med. 195, 1207–1213 (2002).

    Article  CAS  Google Scholar 

  37. Jin, L., McLean, P.A., Neel, B.G. & Wortis, H.H. Sialic acid binding domains of CD22 are required for negative regulation of B cell receptor signaling. J. Exp. Med. 195, 1199–1205 (2002).

    Article  CAS  Google Scholar 

  38. Collins, B.E., Smith, B.A., Bengtson, P. & Paulson, J.C. Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling. Nat. Immunol. 7, 199–206 (2006).

    Article  CAS  Google Scholar 

  39. Ghosh, S., Bandulet, C. & Nitschke, L. Regulation of B cell development and B cell signalling by CD22 and its ligands alpha2,6-linked sialic acids. Int. Immunol. 18, 603–611 (2006).

    Article  CAS  Google Scholar 

  40. Nitschke, L. The role of CD22 and other inhibitory co-receptors in B-cell activation. Curr. Opin. Immunol. 17, 290–297 (2005).

    Article  CAS  Google Scholar 

  41. Chen, J. et al. CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nat. Immunol. 5, 651–657 (2004).

    Article  CAS  Google Scholar 

  42. Cyster, J.G. & Goodnow, C.C. Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity 2, 13–24 (1995).

    Article  CAS  Google Scholar 

  43. Martin, F., Oliver, A.M. & Kearney, J.F. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14, 617–629 (2001).

    Article  CAS  Google Scholar 

  44. Samardzic, T. et al. Reduction of marginal zone B cells in CD22-deficient mice. Eur. J. Immunol. 32, 561–567 (2002).

    Article  CAS  Google Scholar 

  45. Coffman, R.L. et al. The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol. Rev. 102, 5–28 (1988).

    Article  CAS  Google Scholar 

  46. Gerlach, J. et al. B cell defects in SLP65/BLNK-deficient mice can be partially corrected by the absence of CD22, an inhibitory coreceptor for BCR signaling. Eur. J. Immunol. 33, 3418–3426 (2003).

    Article  CAS  Google Scholar 

  47. Kinoshita, T. et al. Monoclonal antibodies to mouse complement receptor type 1 (CR1). Their use in a distribution study showing that mouse erythrocytes and platelets are CR1-negative. J. Immunol. 140, 3066–3072 (1988).

    CAS  PubMed  Google Scholar 

  48. Leptin, M. et al. Monoclonal antibodies specific for murine IgM I. Characterization of antigenic determinants on the four constant domains of the mu heavy chain. Eur. J. Immunol. 14, 534–542 (1984).

    Article  CAS  Google Scholar 

  49. Wellmann, U., Werner, A. & Winkler, T.H. Altered selection processes of B lymphocytes in autoimmune NZB/W mice, despite intact central tolerance against DNA. Eur. J. Immunol. 31, 2800–2810 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Döhler for blastocyst injections; C. Linden and U. Appelt for cell sorting; K. Voss, S. Angermüller and C. Dix for technical help; B. Bochner for Siglec-G cDNA; L. Klein for CD45.1 BALB/c mice; and R. Slany for help with retroviral infection. Supported by the Deutsche Forschungsgemeinschaft (SFB643 and FOR832).

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Authors and Affiliations

  1. Department of Genetics, University of Erlangen, Erlangen, 91058, Germany

    Anja Hoffmann, Julia Jellusova & Lars Nitschke

  2. Wellcome Trust Biocentre, University of Dundee, Dundee, DD1 5EH, UK

    Sheena Kerr, Jiquan Zhang & Paul R Crocker

  3. Department of Genetics, Nikolaus-Fiebiger-Zentrum, University of Erlangen, Erlangen, 91054, Germany

    Florian Weisel, Ute Wellmann & Thomas H Winkler

  4. Zentrum für Operative Medizin, University of Würzburg, Würzburg, 97080, Germany

    Burkhard Kneitz

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  1. Anja Hoffmann
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Contributions

A.H. did experiments and contributed to the writing; S.K., J.J., J.Z., F.W. and U.W. did experiments; T.H.W., B.K. and P.R.C. supervised experiments; and L.N. supervised experiments and wrote the paper.

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Correspondence to Lars Nitschke.

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Supplementary information

Supplementary Fig. 1

Alignment of murine Siglec-G and human Siglec-10. (PDF 109 kb)

Supplementary Fig. 2

Siglec-G targeting strategy and resulting SiglecG-deficient mice. (PDF 245 kb)

Supplementary Fig. 3

Proximal BCR-induced signaling is weaker in B1 cells than in B2 cells, but not substantially altered in Siglecg−/− mice. (PDF 172 kb)

Supplementary Fig. 4

Autoantibodies in Siglecg−/− mice. (PDF 758 kb)

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Hoffmann, A., Kerr, S., Jellusova, J. et al. Siglec-G is a B1 cell–inhibitory receptor that controls expansion and calcium signaling of the B1 cell population. Nat Immunol 8, 695–704 (2007). https://doi.org/10.1038/ni1480

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