Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Aug 1;176(2):427–438. doi: 10.1084/jem.176.2.427

Natural occurrence and origin of somatically mutated memory B cells in mice

PMCID: PMC2119338  PMID: 1500855

Abstract

While most murine peripheral B cells express germline-encoded antibodies of classes M and D (mu+ delta+ cells), small numbers of memory B cells expressing somatically mutated immunoglobulin G antibodies are generated upon T cell-dependent immunization. Analyzing the antibody repertoire of the mu-delta- B cell pool in unimmunized mice, we show that these cells express somatically mutated VH genes and that most of these genes derive from a set of germline VH genes dominantly expressed by mu+delta+ B cells. Thus, class-switched memory B cells are generated in the absence of intentional immunization, presumably in response to environmental antigens. These cells are either recruited from mu+delta+ B cells or selected from newly arising B cells in parallel to the latter, by the same antigens.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen D., Cumano A., Dildrop R., Kocks C., Rajewsky K., Rajewsky N., Roes J., Sablitzky F., Siekevitz M. Timing, genetic requirements and functional consequences of somatic hypermutation during B-cell development. Immunol Rev. 1987 Apr;96:5–22. doi: 10.1111/j.1600-065x.1987.tb00506.x. [DOI] [PubMed] [Google Scholar]
  2. Allen D., Simon T., Sablitzky F., Rajewsky K., Cumano A. Antibody engineering for the analysis of affinity maturation of an anti-hapten response. EMBO J. 1988 Jul;7(7):1995–2001. doi: 10.1002/j.1460-2075.1988.tb03038.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berek C., Berger A., Apel M. Maturation of the immune response in germinal centers. Cell. 1991 Dec 20;67(6):1121–1129. doi: 10.1016/0092-8674(91)90289-b. [DOI] [PubMed] [Google Scholar]
  4. Berek C., Milstein C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev. 1987 Apr;96:23–41. doi: 10.1111/j.1600-065x.1987.tb00507.x. [DOI] [PubMed] [Google Scholar]
  5. Blier P. R., Bothwell A. A limited number of B cell lineages generates the heterogeneity of a secondary immune response. J Immunol. 1987 Dec 15;139(12):3996–4006. [PubMed] [Google Scholar]
  6. Bothwell A. L., Paskind M., Reth M., Imanishi-Kari T., Rajewsky K., Baltimore D. Heavy chain variable region contribution to the NPb family of antibodies: somatic mutation evident in a gamma 2a variable region. Cell. 1981 Jun;24(3):625–637. doi: 10.1016/0092-8674(81)90089-1. [DOI] [PubMed] [Google Scholar]
  7. Capra J. D., Kehoe J. M. Variable region sequences of five human immunoglobulin heavy chains of the VH3 subgroup: definitive identification of four heavy chain hypervariable regions. Proc Natl Acad Sci U S A. 1974 Mar;71(3):845–848. doi: 10.1073/pnas.71.3.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Claflin J. L., George J., Dell C., Berry J. Patterns of mutations and selection in antibodies to the phosphocholine-specific determinant in Proteus morganii. J Immunol. 1989 Nov 1;143(9):3054–3063. [PubMed] [Google Scholar]
  9. Coffman R. L., Cohn M. The class of surface immunoglobulin on virgin and memory B lymphocytes. J Immunol. 1977 May;118(5):1806–1815. [PubMed] [Google Scholar]
  10. Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
  11. Coutinho A. Beyond clonal selection and network. Immunol Rev. 1989 Aug;110:63–87. doi: 10.1111/j.1600-065x.1989.tb00027.x. [DOI] [PubMed] [Google Scholar]
  12. Cumano A., Rajewsky K. Clonal recruitment and somatic mutation in the generation of immunological memory to the hapten NP. EMBO J. 1986 Oct;5(10):2459–2468. doi: 10.1002/j.1460-2075.1986.tb04522.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cumano A., Rajewsky K. Structure of primary anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies in normal and idiotypically suppressed C57BL/6 mice. Eur J Immunol. 1985 May;15(5):512–520. doi: 10.1002/eji.1830150517. [DOI] [PubMed] [Google Scholar]
  14. Esser C., Radbruch A. Immunoglobulin class switching: molecular and cellular analysis. Annu Rev Immunol. 1990;8:717–735. doi: 10.1146/annurev.iy.08.040190.003441. [DOI] [PubMed] [Google Scholar]
  15. Förster I., Vieira P., Rajewsky K. Flow cytometric analysis of cell proliferation dynamics in the B cell compartment of the mouse. Int Immunol. 1989;1(4):321–331. doi: 10.1093/intimm/1.4.321. [DOI] [PubMed] [Google Scholar]
  16. Gu H., Förster I., Rajewsky K. Sequence homologies, N sequence insertion and JH gene utilization in VHDJH joining: implications for the joining mechanism and the ontogenetic timing of Ly1 B cell and B-CLL progenitor generation. EMBO J. 1990 Jul;9(7):2133–2140. doi: 10.1002/j.1460-2075.1990.tb07382.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gu H., Tarlinton D., Müller W., Rajewsky K., Förster I. Most peripheral B cells in mice are ligand selected. J Exp Med. 1991 Jun 1;173(6):1357–1371. doi: 10.1084/jem.173.6.1357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hanahan D., Meselson M. Plasmid screening at high colony density. Methods Enzymol. 1983;100:333–342. doi: 10.1016/0076-6879(83)00066-x. [DOI] [PubMed] [Google Scholar]
  19. Hayakawa K., Ishii R., Yamasaki K., Kishimoto T., Hardy R. R. Isolation of high-affinity memory B cells: phycoerythrin as a probe for antigen-binding cells. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1379–1383. doi: 10.1073/pnas.84.5.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Honjo T., Obata M., Yamawaki-Katoaka Y., Kataoka T., Kawakami T., Takahashi N., Mano Y. Cloning and complete nucleotide sequence of mouse immunoglobulin gamma 1 chain gene. Cell. 1979 Oct;18(2):559–568. doi: 10.1016/0092-8674(79)90072-2. [DOI] [PubMed] [Google Scholar]
  21. Jacob J., Kelsoe G., Rajewsky K., Weiss U. Intraclonal generation of antibody mutants in germinal centres. Nature. 1991 Dec 5;354(6352):389–392. doi: 10.1038/354389a0. [DOI] [PubMed] [Google Scholar]
  22. Kantor A. B. The development and repertoire of B-1 cells (CD5 B cells). Immunol Today. 1991 Nov;12(11):389–391. doi: 10.1016/0167-5699(91)90136-H. [DOI] [PubMed] [Google Scholar]
  23. Kearney J. F., Vakil M. Idiotype-directed interactions during ontogeny play a major role in the establishment of the adult B cell repertoire. Immunol Rev. 1986 Dec;94:39–50. doi: 10.1111/j.1600-065x.1986.tb01163.x. [DOI] [PubMed] [Google Scholar]
  24. Kocks C., Rajewsky K. Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways. Annu Rev Immunol. 1989;7:537–559. doi: 10.1146/annurev.iy.07.040189.002541. [DOI] [PubMed] [Google Scholar]
  25. Kraal G., Weissman I. L., Butcher E. C. Germinal centre B cells: antigen specificity and changes in heavy chain class expression. Nature. 1982 Jul 22;298(5872):377–379. doi: 10.1038/298377a0. [DOI] [PubMed] [Google Scholar]
  26. Linton PJ L., Decker D. J., Klinman N. R. Primary antibody-forming cells and secondary B cells are generated from separate precursor cell subpopulations. Cell. 1989 Dec 22;59(6):1049–1059. doi: 10.1016/0092-8674(89)90761-7. [DOI] [PubMed] [Google Scholar]
  27. MacLennan I. C., Gray D. Antigen-driven selection of virgin and memory B cells. Immunol Rev. 1986 Jun;91:61–85. doi: 10.1111/j.1600-065x.1986.tb01484.x. [DOI] [PubMed] [Google Scholar]
  28. Manser T., Gefter M. L. The molecular evolution of the immune response: idiotope-specific suppression indicates that B cells express germ-line-encoded V genes prior to antigenic stimulation. Eur J Immunol. 1986 Nov;16(11):1439–1444. doi: 10.1002/eji.1830161120. [DOI] [PubMed] [Google Scholar]
  29. Marshak-Rothstein A., Fink P., Gridley T., Raulet D. H., Bevan M. J., Gefter M. L. Properties and applications of monoclonal antibodies directed against determinants of the Thy-1 locus. J Immunol. 1979 Jun;122(6):2491–2497. [PubMed] [Google Scholar]
  30. McHeyzer-Williams M. G., Nossal G. J., Lalor P. A. Molecular characterization of single memory B cells. Nature. 1991 Apr 11;350(6318):502–505. doi: 10.1038/350502a0. [DOI] [PubMed] [Google Scholar]
  31. McKean D., Huppi K., Bell M., Staudt L., Gerhard W., Weigert M. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 1984 May;81(10):3180–3184. doi: 10.1073/pnas.81.10.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Miltenyi S., Müller W., Weichel W., Radbruch A. High gradient magnetic cell separation with MACS. Cytometry. 1990;11(2):231–238. doi: 10.1002/cyto.990110203. [DOI] [PubMed] [Google Scholar]
  33. Nishikawa S., Sasaki Y., Kina T., Amagai T., Katsura Y. A monoclonal antibody against Igh6-4 determinant. Immunogenetics. 1986;23(2):137–139. doi: 10.1007/BF00377976. [DOI] [PubMed] [Google Scholar]
  34. Okumura K., Julius M. H., Tsu T., Herzenberg L. A., Herzenberg L. A. Demonstration that IgG memory is carried by IgG-bearing cells. Eur J Immunol. 1976 Jul;6(7):467–472. doi: 10.1002/eji.1830060704. [DOI] [PubMed] [Google Scholar]
  35. Päbo S., Irwin D. M., Wilson A. C. DNA damage promotes jumping between templates during enzymatic amplification. J Biol Chem. 1990 Mar 15;265(8):4718–4721. [PubMed] [Google Scholar]
  36. Rada C., Gupta S. K., Gherardi E., Milstein C. Mutation and selection during the secondary response to 2-phenyloxazolone. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5508–5512. doi: 10.1073/pnas.88.13.5508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Radic M. Z., Mascelli M. A., Erikson J., Shan H., Shlomchik M., Weigert M. Structural patterns in anti-DNA antibodies from MRL/lpr mice. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 2):933–946. doi: 10.1101/sqb.1989.054.01.108. [DOI] [PubMed] [Google Scholar]
  38. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  39. Schittek B., Rajewsky K. Maintenance of B-cell memory by long-lived cells generated from proliferating precursors. Nature. 1990 Aug 23;346(6286):749–751. doi: 10.1038/346749a0. [DOI] [PubMed] [Google Scholar]
  40. Seijen H. G., Bun J. C., Wubbena A. S., Löhlefink K. G. The germinal center precursor cell is surface mu and delta positive. Adv Exp Med Biol. 1988;237:233–237. doi: 10.1007/978-1-4684-5535-9_35. [DOI] [PubMed] [Google Scholar]
  41. Shan H., Shlomchik M., Weigert M. Heavy-chain class switch does not terminate somatic mutation. J Exp Med. 1990 Aug 1;172(2):531–536. doi: 10.1084/jem.172.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Vieira P., Rajewsky K. Persistence of memory B cells in mice deprived of T cell help. Int Immunol. 1990;2(6):487–494. doi: 10.1093/intimm/2.6.487. [DOI] [PubMed] [Google Scholar]
  43. Weiss U., Rajewsky K. The repertoire of somatic antibody mutants accumulating in the memory compartment after primary immunization is restricted through affinity maturation and mirrors that expressed in the secondary response. J Exp Med. 1990 Dec 1;172(6):1681–1689. doi: 10.1084/jem.172.6.1681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Weiss U., Zoebelein R., Rajewsky K. Accumulation of somatic mutants in the B cell compartment after primary immunization with a T cell-dependent antigen. Eur J Immunol. 1992 Feb;22(2):511–517. doi: 10.1002/eji.1830220233. [DOI] [PubMed] [Google Scholar]
  45. Weissman I. L., Gutman G. A., Friedberg S. H., Jerabek L. Lymphoid tissue architecture. III. Germinal centers, T cells, and thymus-dependent vs thymus-independent antigens. Adv Exp Med Biol. 1976;66:229–237. doi: 10.1007/978-1-4613-4355-4_35. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES