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The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Aug 1;180(2):507–516. doi: 10.1084/jem.180.2.507

Major histocompatibility complex class II expression distinguishes two distinct B cell developmental pathways during ontogeny

PMCID: PMC2191599  PMID: 7913950

Abstract

All mature B cells coexpress major histocompatibility complex (MHC) class II molecules, I-A and I-E, which are restriction elements required for antigen presentation to CD4+ T cells. However, the expression of class II during the early stages of B cell development has been unclear. We demonstrate here that there is a difference in the expression of class II during murine B cell development in the fetal liver and adult bone marrow (BM). These differences define two distinct B cell developmental pathways. The Fetal-type (FT) pathway is characterized by pre-B and immature IgM+ B cells generated in the fetal liver which initially lack all class II expression. In contrast, the Adult-type (AT) pathway is typified by B cells developing in the adult BM which express class II molecules from the pre-B cell stage. In vitro stromal cell cultures of sorted fetal liver and adult BM pro-B cells indicated that the difference in I-A expression during B cell development is intrinsic to the progenitors. In addition, we show that FT B cell development is not restricted to the fetal liver but occurs in the peritoneal cavities, spleens, liver, and BM of young mice up to at least 1 mo of age. The AT B cell development begins to emerge after birth but is, however, restricted to the BM environment. These findings indicate that there are two distinct B cell developmental pathways during ontogeny, each of which could contribute differentially to the immune repertoire and thus the functions of B cell subsets and lineages.

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Selected References

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  1. Benoist C., Mathis D. Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu Rev Immunol. 1990;8:681–715. doi: 10.1146/annurev.iy.08.040190.003341. [DOI] [PubMed] [Google Scholar]
  2. Burrows P. D., Cooper M. D. Regulated expression of cell surface antigens during B cell development. Semin Immunol. 1990 May;2(3):189–195. [PubMed] [Google Scholar]
  3. Dasch J. R., Jones P. P. Independent regulation of IgM, IgD, and Ia antigen expression in cultured immature B lymphocytes. J Exp Med. 1986 Apr 1;163(4):938–951. doi: 10.1084/jem.163.4.938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Desiderio S. V., Yancopoulos G. D., Paskind M., Thomas E., Boss M. A., Landau N., Alt F. W., Baltimore D. Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature. 1984 Oct 25;311(5988):752–755. doi: 10.1038/311752a0. [DOI] [PubMed] [Google Scholar]
  5. Feeney A. J. Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences. J Exp Med. 1990 Nov 1;172(5):1377–1390. doi: 10.1084/jem.172.5.1377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hardy R. R. B cell ontogeny and B cell subsets. Curr Opin Immunol. 1989 Dec;2(2):189–198. doi: 10.1016/0952-7915(89)90187-8. [DOI] [PubMed] [Google Scholar]
  7. Hardy R. R., Carmack C. E., Shinton S. A., Kemp J. D., Hayakawa K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med. 1991 May 1;173(5):1213–1225. doi: 10.1084/jem.173.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hardy R. R., Hayakawa K. A developmental switch in B lymphopoiesis. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11550–11554. doi: 10.1073/pnas.88.24.11550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hardy R. R., Kishimoto T., Hayakawa K. Differentiation of B cell progenitors in vitro: generation of surface IgM+ B cells, including Ly-1 B cells, from Thy-1- asialoGM1+ cells in newborn liver. Eur J Immunol. 1987 Dec;17(12):1769–1774. doi: 10.1002/eji.1830171214. [DOI] [PubMed] [Google Scholar]
  10. Hayakawa K., Carmack C. E., Hyman R., Hardy R. R. Natural autoantibodies to thymocytes: origin, VH genes, fine specificities, and the role of Thy-1 glycoprotein. J Exp Med. 1990 Sep 1;172(3):869–878. doi: 10.1084/jem.172.3.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hayakawa K., Hardy R. R., Herzenberg L. A., Herzenberg L. A. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J Exp Med. 1985 Jun 1;161(6):1554–1568. doi: 10.1084/jem.161.6.1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hayakawa K., Tarlinton D., Hardy R. R. Absence of MHC class II expression distinguishes fetal from adult B lymphopoiesis in mice. J Immunol. 1994 May 15;152(10):4801–4807. [PubMed] [Google Scholar]
  13. Herzenberg L. A., Herzenberg L. A. Toward a layered immune system. Cell. 1989 Dec 22;59(6):953–954. doi: 10.1016/0092-8674(89)90748-4. [DOI] [PubMed] [Google Scholar]
  14. Holmberg D., Forsgren S., Ivars F., Coutinho A. Reactions among IgM antibodies derived from normal, neonatal mice. Eur J Immunol. 1984 May;14(5):435–441. doi: 10.1002/eji.1830140510. [DOI] [PubMed] [Google Scholar]
  15. Hämmerling U., Chin A. F., Abbott J. Ontogeny of murine B lymphocytes: sequence of B-cell differentiation from surface-immunoglobulin-negative precursors to plasma cells. Proc Natl Acad Sci U S A. 1976 Jun;73(6):2008–2012. doi: 10.1073/pnas.73.6.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jeong H. D., Teale J. M. Comparison of the fetal and adult functional B cell repertoires by analysis of VH gene family expression. J Exp Med. 1988 Aug 1;168(2):589–603. doi: 10.1084/jem.168.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kantor A. B., Herzenberg L. A. Origin of murine B cell lineages. Annu Rev Immunol. 1993;11:501–538. doi: 10.1146/annurev.iy.11.040193.002441. [DOI] [PubMed] [Google Scholar]
  18. Kantor A. B., Stall A. M., Adams S., Herzenberg L. A., Herzenberg L. A. Differential development of progenitor activity for three B-cell lineages. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3320–3324. doi: 10.1073/pnas.89.8.3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kara C. J., Glimcher L. H. Regulation of MHC class II gene transcription. Curr Opin Immunol. 1991 Feb;3(1):16–21. doi: 10.1016/0952-7915(91)90070-h. [DOI] [PubMed] [Google Scholar]
  20. Kaufman J. F., Auffray C., Korman A. J., Shackelford D. A., Strominger J. The class II molecules of the human and murine major histocompatibility complex. Cell. 1984 Jan;36(1):1–13. doi: 10.1016/0092-8674(84)90068-0. [DOI] [PubMed] [Google Scholar]
  21. Kearney J. F., Cooper M. D., Klein J., Abney E. R., Parkhouse R. M., Lawton A. R. Ontogeny of Ia and IgD on IgM-bearing B lymphocytes in mice. J Exp Med. 1977 Jul 1;146(1):297–301. doi: 10.1084/jem.146.1.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kincade P. W. Formation of B lymphocytes in fetal and adult life. Adv Immunol. 1981;31:177–245. doi: 10.1016/s0065-2776(08)60921-9. [DOI] [PubMed] [Google Scholar]
  23. Lala P. K., Johnson G. R., Battye F. L., Nossal G. J. Maturation of B lymphocytes. I. Concurrent appearance of increasing Ig, Ia, and mitogen responsiveness. J Immunol. 1979 Jan;122(1):334–341. [PubMed] [Google Scholar]
  24. Lam K. P., Herzenberg L. A., Stall A. M. A high frequency of hybridomas from M54 mu heavy chain transgenic mice initially co-express transgenic and rearranged endogenous mu genes. Int Immunol. 1993 Sep;5(9):1011–1022. doi: 10.1093/intimm/5.9.1011. [DOI] [PubMed] [Google Scholar]
  25. Li Y. S., Hayakawa K., Hardy R. R. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J Exp Med. 1993 Sep 1;178(3):951–960. doi: 10.1084/jem.178.3.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Meek K. Analysis of junctional diversity during B lymphocyte development. Science. 1990 Nov 9;250(4982):820–823. doi: 10.1126/science.2237433. [DOI] [PubMed] [Google Scholar]
  27. Mengle-Gaw L., McDevitt H. O. Genetics and expression of mouse Ia antigens. Annu Rev Immunol. 1985;3:367–396. doi: 10.1146/annurev.iy.03.040185.002055. [DOI] [PubMed] [Google Scholar]
  28. Miki N., Hatano M., Wakita K., Imoto S., Nishikawa S., Nishikawa S., Tokuhisa T. Role of I-A molecules in early stages of B cell maturation. J Immunol. 1992 Aug 1;149(3):801–807. [PubMed] [Google Scholar]
  29. Mond J. J., Kessler S., Finkelman F. D., Paul W. E., Scher I. Heterogeneity of Ia expression on normal B cells, neonatal B cells, and on cells from B cell-defective CBA/N mice. J Immunol. 1980 Apr;124(4):1675–1682. [PubMed] [Google Scholar]
  30. Nossal G. J. Cellular mechanisms of immunologic tolerance. Annu Rev Immunol. 1983;1:33–62. doi: 10.1146/annurev.iy.01.040183.000341. [DOI] [PubMed] [Google Scholar]
  31. Oltz E. M., Yancopoulos G. D., Morrow M. A., Rolink A., Lee G., Wong F., Kaplan K., Gillis S., Melchers F., Alt F. W. A novel regulatory myosin light chain gene distinguishes pre-B cell subsets and is IL-7 inducible. EMBO J. 1992 Jul;11(7):2759–2767. doi: 10.1002/j.1460-2075.1992.tb05341.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
  33. Pike B. L., Kay T. W., Nossal G. J. Relative sensitivity of fetal and newborn mice to induction of hapten-specific B cell tolerance. J Exp Med. 1980 Nov 1;152(5):1407–1412. doi: 10.1084/jem.152.5.1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schwartz R. H. T-lymphocyte recognition of antigen in association with gene products of the major histocompatibility complex. Annu Rev Immunol. 1985;3:237–261. doi: 10.1146/annurev.iy.03.040185.001321. [DOI] [PubMed] [Google Scholar]
  35. Solvason N., Lehuen A., Kearney J. F. An embryonic source of Ly1 but not conventional B cells. Int Immunol. 1991 Jun;3(6):543–550. doi: 10.1093/intimm/3.6.543. [DOI] [PubMed] [Google Scholar]
  36. Strasser A., Rolink A., Melchers F. One synchronous wave of B cell development in mouse fetal liver changes at day 16 of gestation from dependence to independence of a stromal cell environment. J Exp Med. 1989 Dec 1;170(6):1973–1986. doi: 10.1084/jem.170.6.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tarlinton D. Direct demonstration of MHC class II surface expression on murine pre-B cells. Int Immunol. 1993 Dec;5(12):1629–1635. doi: 10.1093/intimm/5.12.1629. [DOI] [PubMed] [Google Scholar]
  38. Whitlock C., Denis K., Robertson D., Witte O. In vitro analysis of murine B-cell development. Annu Rev Immunol. 1985;3:213–235. doi: 10.1146/annurev.iy.03.040185.001241. [DOI] [PubMed] [Google Scholar]

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