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Absence of marginal zone B cells in Pyk-2–deficient mice defines their role in the humoral response

Nature Immunology volume 1, pages 31–36 (2000)Cite this article

Abstract

The lymphoid organs contain specialized microanatomic structures composed of lymphoid, myeloid and stromal cells that are vital to the generation of an effective adaptive immune response. Although the existence of these specialized structures has been known for over a century, the developmental signals that generate them and the specific roles of these structures in the immune response have remained largely elusive. Because of their position adjacent to the marginal sinuses, marginal zone B (MZB) cells are amongst the first population of cells seen by blood born antigens and are presumed to have a critical role in host defense against bacterial pathogens. Here we demonstrate that a deficiency of the tyrosine kinase (Pyk-2) results in a cell autonomous defect of MZB cell production. In response to repetitive polysaccharide antigens (T-independent type II (TI-II)) Pyk-2–deficient mice displayed marked suppression of IgM, IgG3 and IgG2a production. Furthermore, complement receptor engagement proved necessary for the specific targeting of polysaccharide antigens to MZB cells. These results suggest how innate immune responses mediated through complement coupling are translated into an adaptive response by MZB cells, and provide a potential mechanism for the T cell independence of humoral responses to polysaccharide antigens.

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Figure 1: Defect of MZB cells in Pyk-2−/− mice.
Figure 2: MZB cell defect is lymphocyte autonomous.
Figure 3: Defective humoral immune response in the absence of Pyk-2.
Figure 4: Antigen localization in WT, C3-, CR1/CR2- and Pyk-2–deficient mice.
Figure 5: Defective TI-II response in C3−/− mice.

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References

  1. MacLennan, I.C. B-cell receptor regulation of peripheral B cells. Curr. Opin. Immunol. 10, 220–225 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Guinamard, R. et al. B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. J. Exp. Med. 189, 1461–1466 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bleul, C.C., Schultze, J.L. & Springer, T.A. B lymphocyte chemotaxis regulated in association with microanatomic localization, differentiation state, and B cell receptor engagement. J. Exp. Med. 187, 753–762 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Forster, R. et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Ma, Q. et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc. Natl Acad. Sci. USA 95, 9448–9453 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lalor, P.A. & Morahan, G. The peritoneal Ly-1 (CD5) B cell repertoire is unique among murine B cell repertoires. Eur. J. Immunol. 20, 485–492 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Oliver, A.M., Martin, F. & Kearney, J.F. IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J.Immunol. 162, 7198–7207 (1999).

    CAS  PubMed  Google Scholar 

  8. Kawabe, T. et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Hayakawa, K., Hardy, R.R., Parks, D.R. & Herzenberg, L.A. The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice. J. Exp. Med. 157, 202–218 (1983).

    Article  CAS  PubMed  Google Scholar 

  10. Qin, X.F., Reichlin, A., Luo, Y., Roeder, R.G. & Nussenzweig, M.C. OCA-B integrates B cell antigen receptor-, CD40L- and IL 4-mediated signals for the germinal center pathway of B cell development. EMBO J. 17, 5066–5075 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dikic, I., Tokiwa, G., Lev, S., Courtneidge, S.A. & Schlessinger, J. A role for Pyk2 Src in linking G-protein-coupled receptors with MAP kinase activation. Nature 383, 547–550 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Lev, S. et al. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions [see comments]. Nature 376, 737–745 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Lev, S. et al. Identification of a novel family of targets of PYK2 related to Drosophila retinal degeneration B (rdgB) protein. Mol. Cell Biol. 19, 2278–2288 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Davis, C.B. et al. Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5. J. Exp. Med. 186, 1793–1798 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ma, E.A., Lou, O., Berg, N.N. & Ostergaard, H.L. Cytotoxic T lymphocytes express a beta3 integrin which can induce the phosphorylation of focal adhesion kinase and the related PYK2. Eur. J. Immunol. 27, 329–335 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Okigaki, M. et al. Pyk2 regulates multiple signalling events crucial for macrophage morphology, migration and function. Nature Cell Biol. (Submitted).

  17. Ma, Q., Jones, D. & Springer, T.A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10, 463–471 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Zou, Y.R., Kottmann, A.H., Kuroda, M., Taniuchi, I. & Littman, D.R. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development [see comments]. Nature 393, 595–599 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Tachibana, K. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract [see comments]. Nature 393, 591–594 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Oliver, A.M., Martin, F., Gartland, G.L., Carter, R.H. & Kearney, J.F. Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory. Eur. J. Immunol. 27, 2366–2374 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Roark, J.H. et al. CD1.1 expression by mouse antigen-presenting cells and marginal zone B cells. J. Immunol. 160, 3121–3127 (1998).

    CAS  PubMed  Google Scholar 

  23. Smith, K.G., Hewitson, T.D., Nossal, G.J. & Tarlinton, D.M. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur. J. Immunol. 26, 444–448 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Lane, P.J., Gray, D., Oldfield, S. & MacLennan, I.C. Differences in the recruitment of virgin B cells into antibody responses to thymus-dependent and thymus-independent type-2 antigens. Eur. J. Immunol. 16, 1569–1575 (1986).

    Article  CAS  PubMed  Google Scholar 

  25. Ilgen, C.L., Bossen, E.H., Rowlands, D.T.J. & Burkholder, P.M. Isolation and characterization of C4-synthesizing cells from guinea-pig spleen. Immunology 26, 659–665 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ochsenbein, A.F. et al. Protective T cell-independent antiviral antibody responses are dependent on complement. J. Exp. Med. 190, 1165–1174 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dempsey, P.W., Allison, M.E., Akkaraju, S., Goodnow, C.C. & Fearon, D.T. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271, 348–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Inaoki, M., Sato, S., Weintraub, B.C., Goodnow, C.C. & Tedder, T.F. CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J. Exp. Med. 186, 1923–1931 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Campbell, J.J. et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Liakka, K.A. The integrin subunits alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, alpha V, beta 1 and beta 3 in fetal, infant and adult human spleen as detected by immunohistochemistry. Differentiation 56, 183–190 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Gunn, M.D. et al. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 391, 799–803 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Opstelten, D., Niewiadomska, A., Kwong, A.Y.H. & Nagasawa, T. Proc. 10th Int. Congr. Immunol. 63–69 (1998).

  33. Makowska, A., Faizunnessa, N.N., Anderson, P., Midtvedt, T. & Cardell, S. CD1high B cells: a population of mixed origin. Eur. J. Immunol. 29, 3285–3294 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Rickert, R.C., Rajewsky, K. & Roes, J. Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376, 352–355 1995).

    Article  CAS  PubMed  Google Scholar 

  35. Scher, I. The CBA/N mouse strain: an experimental model illustrating the influence of the X-chromosome on immunity. Adv. Immunol. 33, 1–71 (1982).

    Article  CAS  PubMed  Google Scholar 

  36. Prior, L., Pierson, S., Woodland, R.T. & Riggs, J. Rapid restoration of B-cell function in XID mice by intravenous transfer of peritoneal cavity B cells. Immunology 83, 180–183 (1994). (Published erratum appears in Immunology 84, 172 (1995).)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Carroll, M.C. & Prodeus, A.P. Linkages of innate and adaptive immunity. Curr. Opin. Immunol. 10, 36–40 (1998).

  38. Takai, T., Ono, M., Hikida, M., Ohmori, H. & Ravetch, J.V. Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice. Nature 379, 346–349 (1996).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful for the comments of R. Steinman and M. Nussenzweig on this manuscript and for the assistance provided by P. Kaloudis and C. Ritter in preparing it. These studies were supported by grants from the NIH . R.G. is a fellow of the Irvington Institute for Immunology.

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Author notes

  1. Rodolphe Guinamard and Mitsuhiko Okigaki: These authors contributed equally to the work.

Authors and Affiliations

  1. Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Ave, New York, 10021, NY, USA

    Rodolphe Guinamard & Jeffrey V. Ravetch

  2. Department of Pharmacology, New York University Medical Center, 550 First Ave, New York, 10016, NY, USA

    Mitsuhiko Okigaki & Joseph Schlessinger

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  1. Rodolphe Guinamard
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Correspondence to Jeffrey V. Ravetch.

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Guinamard, R., Okigaki, M., Schlessinger, J. et al. Absence of marginal zone B cells in Pyk-2–deficient mice defines their role in the humoral response. Nat Immunol 1, 31–36 (2000). https://doi.org/10.1038/76882

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