Article | Published:

The IgM receptor FcμR limits tonic BCR signaling by regulating expression of the IgM BCR

Nature Immunology volume 18, pages 321333 (2017) | Download Citation

Abstract

The FcμR receptor for the crystallizable fragment (Fc) of immunoglobulin M (IgM) can function as a cell-surface receptor for secreted IgM on a variety of cell types. We found here that FcμR was also expressed in the trans-Golgi network of developing B cells, where it constrained transport of the IgM-isotype BCR (IgM-BCR) but not of the IgD-isotype BCR (IgD-BCR). In the absence of FcμR, the surface expression of IgM-BCR was increased, which resulted in enhanced tonic BCR signaling. B-cell-specific deficiency in FcμR enhanced the spontaneous differentiation of B-1 cells, which resulted in increased serum concentrations of natural IgM and dysregulated homeostasis of B-2 cells; this caused the spontaneous formation of germinal centers, increased titers of serum autoantibodies and excessive accumulation of B cells. Thus, FcμR serves as a critical regulator of B cell biology by constraining the transport and cell-surface expression of IgM-BCR.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination. Blood 118, 598–608 (2011).

  2. 2.

    et al. Antiapoptotic function of Toso (Faim3) in death receptor signaling. Blood 119, 1790–1791 (2012).

  3. 3.

    et al. Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells. Immunity 8, 461–471 (1998).

  4. 4.

    et al. Identity of the elusive IgM Fc receptor (FcmuR) in humans. J. Exp. Med. 206, 2779–2793 (2009).

  5. 5.

    , , & FcμR (Toso/Faim3) is not an inhibitor of Fas-mediated cell death in mouse T and B cells. Blood 121, 2368–2370 (2013).

  6. 6.

    et al. Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses. Proc. Natl. Acad. Sci. USA 109, E2699–E2706 (2012).

  7. 7.

    et al. Altered Ig levels and antibody responses in mice deficient for the Fc receptor for IgM (FcμR). Proc. Natl. Acad. Sci. USA 109, 15882–15887 (2012).

  8. 8.

    et al. Mouse IgM Fc receptor, FCMR, promotes B cell development and modulates antigen-driven immune responses. J. Immunol. 190, 987–996 (2013).

  9. 9.

    et al. Involvement of Toso in activation of monocytes, macrophages, and granulocytes. Proc. Natl. Acad. Sci. USA 110, 2593–2598 (2013).

  10. 10.

    et al. Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells. Proc. Natl. Acad. Sci. USA 111, 1060–1065 (2014).

  11. 11.

    et al. Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection. Cell Death Differ. 22, 164–173 (2015).

  12. 12.

    et al. FcμR interacts and cooperates with the B cell receptor To promote B cell survival. J. Immunol. 194, 3096–3101 (2015).

  13. 13.

    & Tyrosine sulfation is a trans-Golgi-specific protein modification. J. Cell Biol. 105, 2655–2664 (1987).

  14. 14.

    , & In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).

  15. 15.

    & Regulation of B-cell fate by antigen-receptor signals. Nat. Rev. Immunol. 2, 945–956 (2002).

  16. 16.

    , & TOSO, the Fcmicro receptor, is highly expressed on chronic lymphocytic leukemia B cells, internalizes upon IgM binding, shuttles to the lysosome, and is downregulated in response to TLR activation. J. Immunol. 187, 4040–4050 (2011).

  17. 17.

    et al. Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcμR) in patients with chronic lymphocytic leukemia. Blood 118, 4902–4909 (2011).

  18. 18.

    et al. Identification of TOSO/FAIM3 as an Fc receptor for IgM. Int. Immunol. 22, 149–156 (2010).

  19. 19.

    , & Bone marrow pre-B lymphocytes synthesize immunoglobulin mu chains of membrane type with different properties and intracellular pathways. EMBO J. 4, 361–368 (1985).

  20. 20.

    , & Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction. J. Immunol. 194, 1489–1502 (2015).

  21. 21.

    , & A guide to super-resolution fluorescence microscopy. J. Cell Biol. 190, 165–175 (2010).

  22. 22.

    et al. Enhanced B-1 cell development, but impaired IgG antibody responses in mice deficient in secreted IgM. J. Immunol. 160, 4776–4787 (1998).

  23. 23.

    , & A mouse monoclonal antibody specific for an allotypic determinant of the Igha allele of murine IgM: genetic and functional analysis of Igh-6a epitopes using anti-IgM monoclonal antibodies. Hybridoma 10, 121–135 (1991).

  24. 24.

    & Dual role for B-1a cells in immunity to influenza virus infection. J. Exp. Med. 205, 3053–3064 (2008).

  25. 25.

    , , & Feedback regulation of murine Ly-1 B cell development. Eur. J. Immunol. 19, 507–513 (1989).

  26. 26.

    , & . IgM in bone marrow-derived lymphocytes. Synthesis, surface deposition, turnover and carbohydrate composition in unstimulated mouse B cells. Eur. J. Immunol. 4, 170–180 (1974).

  27. 27.

    , , , & B cell activation involves nanoscale receptor reorganizations and inside-out signaling by Syk. eLife 3, e02069 (2014).

  28. 28.

    & Drosophila S2 Schneider cells: a useful tool for rebuilding and redesigning approaches in synthetic biology. Methods Mol. Biol. 813, 331–341 (2012).

  29. 29.

    et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

  30. 30.

    , & Role of PI3K in the generation and survival of B cells. Immunol. Rev. 237, 55–71 (2010).

  31. 31.

    New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol. 13, 65–70 (2003).

  32. 32.

    et al. Bim, a proapoptotic protein, up-regulated via transcription factor E2F1-dependent mechanism, functions as a prosurvival molecule in cancer. J. Biol. Chem. 288, 368–381 (2013).

  33. 33.

    , , & Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627–644 (2009).

  34. 34.

    et al. Positive selection of natural autoreactive B cells. Science 285, 113–116 (1999).

  35. 35.

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

  36. 36.

    et al. B-1 and B-2 cell-derived immunoglobulin M antibodies are nonredundant components of the protective response to influenza virus infection. J. Exp. Med. 192, 271–280 (2000).

  37. 37.

    et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science 286, 2156–2159 (1999).

  38. 38.

    & The follicular versus marginal zone B lymphocyte cell fate decision. Nat. Rev. Immunol. 9, 767–777 (2009).

  39. 39.

    et al. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc. Natl. Acad. Sci. USA 97, 1184–1189 (2000).

  40. 40.

    et al. B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. J. Exp. Med. 213, 733–750 (2016).

  41. 41.

    et al. Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1. J. Immunol. 196, 2031–2040 (2016).

  42. 42.

    et al. Responsiveness of B cells is regulated by the hinge region of IgD. Nat. Immunol. 16, 534–543 (2015).

  43. 43.

    & B cells turn off virgin but not memory T cells. Science 258, 1156–1159 (1992).

  44. 44.

    et al. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc. Natl. Acad. Sci. USA 96, 2250–2255 (1999).

  45. 45.

    , & B-1 cells: unique origins and functions. Semin. Immunol. 8, 45–59 (1996).

  46. 46.

    , , , & B-1 cells in the bone marrow are a significant source of natural IgM. Eur. J. Immunol. 42, 120–129 (2012).

  47. 47.

    et al. Enumeration and characterization of virus-specific B cells by multicolor flow cytometry. J. Immunol. Methods 303, 40–52 (2005).

  48. 48.

    , & Measuring protein mobility by photobleaching GFP chimeras in living cells. Current Protocols in Cell Biology (eds. Bonifacino, J.S. et al.) Ch. 21, Unit 21 (John Wiley and Sons, 2003).

  49. 49.

    , , , & Constrained diffusion or immobile fraction on cell surfaces: a new interpretation. Biophys. J. 70, 2767–2773 (1996).

  50. 50.

    et al. Monitoring the dynamics and mobility of membrane proteins tagged with green fluorescent protein. Methods Cell Biol. 58, 261–281 (1999).

  51. 51.

    et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).

Download references

Acknowledgements

We thank A. Spinner for help with flow cytometry; A. Treister for FlowJo software; R. Pohlmeyer for sharing flow cytometry data; J. Yang (University of Freiburg) for the GFP-IgD plasmid; M. Cavallari for help with image analysis; H. Kubagawa (Deutsches Rheuma Forschungszentrum) for BM from mice with global Fcmr deficiency; and the UC Davis Mouse Biology Program for generating Fcmrflx/flxCd19-Cre mice. Supported by the US National Institutes of Health (AI51354, AI85568 and U19AI109962 to N.B.), the UC Davis Graduate Group in Immunology, a Vietnamese Education Fellowship (T.T.T.N.), a UC Davis Chancellor's Fellowship (N.B.), the Excellence Initiative of the German Federal and State Governments (EXC 294), the European Research Council (322972) and the DFG (TRR130 and project 111026 of the German Cancer Aid to M.R.).

Author information

Affiliations

  1. Center for Comparative Medicine, University of California, Davis, Davis, California, USA.

    • Trang T T Nguyen
    •  & Nicole Baumgarth
  2. Graduate Group in Immunology, University of California, Davis, Davis, California, USA.

    • Trang T T Nguyen
    • , Patricia A Castillo
    • , Charles L Bevins
    •  & Nicole Baumgarth
  3. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.

    • Kathrin Kläsener
    •  & Michael Reth
  4. Department of Molecular Immunology, Institute of Biology III at the Faculty of Biology of the University of Freiburg, Freiburg, Germany.

    • Kathrin Kläsener
    •  & Michael Reth
  5. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.

    • Kathrin Kläsener
    • , Christa Zürn
    •  & Michael Reth
  6. Department of Medical Microbiology & Immunology, University of California, Davis, California, USA.

    • Patricia A Castillo
    •  & Charles L Bevins
  7. Department of Anatomy, Physiology & Cell Biology, University of California, Davis, California, USA.

    • Ingrid Brust-Mascher
    •  & Colin Reardon
  8. Comparative Pathology Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.

    • Denise M Imai
    •  & Nicole Baumgarth
  9. Department of Pathology, Microbiology & Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.

    • Nicole Baumgarth

Authors

  1. Search for Trang T T Nguyen in:

  2. Search for Kathrin Kläsener in:

  3. Search for Christa Zürn in:

  4. Search for Patricia A Castillo in:

  5. Search for Ingrid Brust-Mascher in:

  6. Search for Denise M Imai in:

  7. Search for Charles L Bevins in:

  8. Search for Colin Reardon in:

  9. Search for Michael Reth in:

  10. Search for Nicole Baumgarth in:

Contributions

T.T.T.N. and N.B. designed experiments, analyzed data and wrote the manuscripts; K.K., C.L.B. and M.R. provided help with experimental design; T.T.T.N., K.K., C.Z. and P.A.C. performed experiments; I.B.-M. and C.R. helped with STED and confocal microscopy and image analysis; D.M.I. performed pathological evaluation of Fcmrflx/flxCd19-Cre mice; and all authors provided edits to the manuscript.

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.3677

Further reading