Fetal liver pro-B and pre-B lymphocyte clones: expression of lymphoid-specific genes, surface markers, growth requirements, colonization of the bone marrow, and generation of B lymphocytes in vivo and in vitro (original) (raw)

Abstract

We describe here the development and characterization of the FLS4.1 stromal line derived from 15-day fetal liver of BALB/c embryos and defined culture conditions that efficiently support the cloning and long-term growth of nontransformed B-220+ 14-day fetal liver cells at two stages of B-cell development, namely, pro-B lymphocytes (immunoglobulin [Ig] genes in germ line configuration) and pre-B cells (JH-rearranged genes with both light-chain Ig genes in the germ line state). All B-cell precursor clones require recombinant interleukin-7 (rIL-7) and FLS4.1 stromal cells for continuous growth in culture, but pro-B lymphocyte clones can also proliferate in rIL-3. None proliferate in rIL-1, rIL-2, rIL-4, rIL-5, rIL-6, or leukemia inhibitory factor. FLS4.1 stromal cells synthesize mRNA for Steel factor but not for IL-1 to IL-7; all pro-B and pre-B clones express c-Kit, the receptor for Steel factor, and a c-Kit-specific antibody inhibits the enhanced proliferative response of fetal liver B-220+ B-cell precursors supported by FLS4.1 stromal cells and exogenous rIL-7 but does not affect that promoted by rIL-7 alone. Northern (RNA) blot analysis of the expression of the MB-1, lambda 5, Vpre-B, c mu, RAG-1, and RAG-2 genes in pro-B and pre-B clones show that transcription of the MB-1 gene precedes IgH gene rearrangement and RNA synthesis from c mu, RAG-1, RAG-2, lambda 5, and Vpre-B genes. All clones at the pre-B-cell stage synthesize mRNA for c mu, RAG-1, and RAG-2 genes; transcription of the lambda 5 and Vpre-B genes seems to start after D-to-JH rearrangement in B-cell precursors, indicating that the proteins encoded by either gene are not required for B-cell progenitors to undergo D-to-JH gene rearrangement. These findings mark transcription of the MB-1 gene as one of the earliest molecular events in commitment to develop along the B-lymphocyte pathway. Indeed, both pro-B and pre-B clones can generate in vitro and in vivo B lymphocytes but not T lymphocytes; moreover, these clones do not express the CD3-gamma T-cell-specific gene, nor do they have rearranged gamma, delta, or beta T-cell antigen receptor genes.

518

Images in this article

Selected References

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

  1. Alt F. W., Yancopoulos G. D., Blackwell T. K., Wood C., Thomas E., Boss M., Coffman R., Rosenberg N., Tonegawa S., Baltimore D. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 1984 Jun;3(6):1209–1219. doi: 10.1002/j.1460-2075.1984.tb01955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bothwell A. L., Paskind M., Reth M., Imanishi-Kari T., Rajewsky K., Baltimore D. Somatic variants of murine immunoglobulin lambda light chains. Nature. 1982 Jul 22;298(5872):380–382. doi: 10.1038/298380a0. [DOI] [PubMed] [Google Scholar]
  3. Cherayil B. J., Pillai S. The omega/lambda 5 surrogate immunoglobulin light chain is expressed on the surface of transitional B lymphocytes in murine bone marrow. J Exp Med. 1991 Jan 1;173(1):111–116. doi: 10.1084/jem.173.1.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dorshkind K. Regulation of hemopoiesis by bone marrow stromal cells and their products. Annu Rev Immunol. 1990;8:111–137. doi: 10.1146/annurev.iy.08.040190.000551. [DOI] [PubMed] [Google Scholar]
  5. Gutierrez J. C., Palacios R. Heterogeneity of thymic epithelial cells in promoting T-lymphocyte differentiation in vivo. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):642–646. doi: 10.1073/pnas.88.2.642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hunt P., Robertson D., Weiss D., Rennick D., Lee F., Witte O. N. A single bone marrow-derived stromal cell type supports the in vitro growth of early lymphoid and myeloid cells. Cell. 1987 Mar 27;48(6):997–1007. doi: 10.1016/0092-8674(87)90708-2. [DOI] [PubMed] [Google Scholar]
  7. Karasuyama H., Kudo A., Melchers F. The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain. J Exp Med. 1990 Sep 1;172(3):969–972. doi: 10.1084/jem.172.3.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  9. Katoh S., Tominaga A., Migita M., Kudo A., Takatsu K. Conversion of normal Ly-1-positive B-lineage cells into Ly-1-positive macrophages in long-term bone marrow cultures. Dev Immunol. 1990;1(2):113–125. doi: 10.1155/1990/28760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Kincade P. W., Lee G., Pietrangeli C. E., Hayashi S., Gimble J. M. Cells and molecules that regulate B lymphopoiesis in bone marrow. Annu Rev Immunol. 1989;7:111–143. doi: 10.1146/annurev.iy.07.040189.000551. [DOI] [PubMed] [Google Scholar]
  12. Krissansen G. W., Owen M. J., Fink P. J., Crumpton M. J. Molecular cloning of the cDNA encoding the T3 gamma subunit of the mouse T3/T cell antigen receptor complex. J Immunol. 1987 May 15;138(10):3513–3518. [PubMed] [Google Scholar]
  13. Kruger M. G., Riley R. L., Riley E. A., Elia J. M. Bone marrow stromal cells modulate both kappa light chain and Ly1 antigen expression on Ly1+ pre-B cell lines in vitro. Blood. 1990 Jul 15;76(2):383–392. [PubMed] [Google Scholar]
  14. Kudo A., Melchers F. A second gene, VpreB in the lambda 5 locus of the mouse, which appears to be selectively expressed in pre-B lymphocytes. EMBO J. 1987 Aug;6(8):2267–2272. doi: 10.1002/j.1460-2075.1987.tb02500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lang R. B., Stanton L. W., Marcu K. B. On immunoglobulin heavy chain gene switching: two gamma 2b genes are rearranged via switch sequences in MPC-11 cells but only one is expressed. Nucleic Acids Res. 1982 Jan 22;10(2):611–630. doi: 10.1093/nar/10.2.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lee G., Namen A. E., Gillis S., Ellingsworth L. R., Kincade P. W. Normal B cell precursors responsive to recombinant murine IL-7 and inhibition of IL-7 activity by transforming growth factor-beta. J Immunol. 1989 Jun 1;142(11):3875–3883. [PubMed] [Google Scholar]
  17. Lennon G. G., Perry R. P. The temporal order of appearance of transcripts from unrearranged and rearranged Ig genes in murine fetal liver. J Immunol. 1990 Mar 1;144(5):1983–1987. [PubMed] [Google Scholar]
  18. Marcu K. B., Banerji J., Penncavage N. A., Lang R., Arnheim N. 5' flanking region of immunoglobulin heavy chain constant region genes displays length heterogeneity in germlines of inbred mouse strains. Cell. 1980 Nov;22(1 Pt 1):187–196. doi: 10.1016/0092-8674(80)90167-1. [DOI] [PubMed] [Google Scholar]
  19. Martin F. H., Suggs S. V., Langley K. E., Lu H. S., Ting J., Okino K. H., Morris C. F., McNiece I. K., Jacobsen F. W., Mendiaz E. A. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell. 1990 Oct 5;63(1):203–211. doi: 10.1016/0092-8674(90)90301-t. [DOI] [PubMed] [Google Scholar]
  20. McKearn J. P., McCubrey J., Fagg B. Enrichment of hematopoietic precursor cells and cloning of multipotential B-lymphocyte precursors. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7414–7418. doi: 10.1073/pnas.82.21.7414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Meeker T. C., Hardy D., Willman C., Hogan T., Abrams J. Activation of the interleukin-3 gene by chromosome translocation in acute lymphocytic leukemia with eosinophilia. Blood. 1990 Jul 15;76(2):285–289. [PubMed] [Google Scholar]
  22. Miyake K., Medina K. L., Hayashi S., Ono S., Hamaoka T., Kincade P. W. Monoclonal antibodies to Pgp-1/CD44 block lympho-hemopoiesis in long-term bone marrow cultures. J Exp Med. 1990 Feb 1;171(2):477–488. doi: 10.1084/jem.171.2.477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Namen A. E., Lupton S., Hjerrild K., Wignall J., Mochizuki D. Y., Schmierer A., Mosley B., March C. J., Urdal D., Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988 Jun 9;333(6173):571–573. doi: 10.1038/333571a0. [DOI] [PubMed] [Google Scholar]
  24. Nomura J., Matsuo T., Kubota E., Kimoto M., Sakaguchi N. Signal transmission through the B cell-specific MB-1 molecule at the pre-B cell stage. Int Immunol. 1991 Feb;3(2):117–126. doi: 10.1093/intimm/3.2.117. [DOI] [PubMed] [Google Scholar]
  25. Nossal G. J., Pike B. L. Studies on the differentiation of B lymphocytes in the mouse. Immunology. 1973 Jul;25(1):33–45. [PMC free article] [PubMed] [Google Scholar]
  26. Oettinger M. A., Schatz D. G., Gorka C., Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. doi: 10.1126/science.2360047. [DOI] [PubMed] [Google Scholar]
  27. Osmond D. G. B cell development in the bone marrow. Semin Immunol. 1990 May;2(3):173–180. [PubMed] [Google Scholar]
  28. Owen J. J., Cooper M. D., Raff M. C. In vitro generation of B lymphocytes in mouse foetal liver, a mammalian 'bursa equivalent'. Nature. 1974 May 24;249(455):361–363. doi: 10.1038/249361a0. [DOI] [PubMed] [Google Scholar]
  29. Palacios R., Karasuyama H., Rolink A. Ly1+ PRO-B lymphocyte clones. Phenotype, growth requirements and differentiation in vitro and in vivo. EMBO J. 1987 Dec 1;6(12):3687–3693. doi: 10.1002/j.1460-2075.1987.tb02702.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Palacios R., Leu T. CC11: a monoclonal antibody specific for interleukin 3-sensitive mouse cells defines two major populations of B cell precursors in the bone marrow. Immunol Rev. 1986 Oct;93:125–146. doi: 10.1111/j.1600-065x.1986.tb01505.x. [DOI] [PubMed] [Google Scholar]
  31. Palacios R., Pelkonen J. Prethymic and intrathymic mouse T-cell progenitors. Growth requirements and analysis of the expression of genes encoding TCR/T3 components and other T-cell-specific molecules. Immunol Rev. 1988 Aug;104:5–27. doi: 10.1111/j.1600-065x.1988.tb00757.x. [DOI] [PubMed] [Google Scholar]
  32. Palacios R., Steinmetz M. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell. 1985 Jul;41(3):727–734. doi: 10.1016/s0092-8674(85)80053-2. [DOI] [PubMed] [Google Scholar]
  33. Palacios R., Stuber S., Rolink A. The epigenetic influences of bone marrow and fetal liver stroma cells on the developmental potential of Ly-1+ pro-B lymphocyte clones. Eur J Immunol. 1989 Feb;19(2):347–356. doi: 10.1002/eji.1830190220. [DOI] [PubMed] [Google Scholar]
  34. Pelkonen J., Sideras P., Rammensee H. G., Karjalainen K., Palacios R. Thymocyte clones from 14-day mouse embryos. I. State of T cell receptor genes, surface markers, and growth requirements. J Exp Med. 1987 Nov 1;166(5):1245–1258. doi: 10.1084/jem.166.5.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rennick D., Jackson J., Moulds C., Lee F., Yang G. IL-3 and stromal cell-derived factor synergistically stimulate the growth of pre-B cell lines cloned from long-term lymphoid bone marrow cultures. J Immunol. 1989 Jan 1;142(1):161–166. [PubMed] [Google Scholar]
  36. Rolink A., Kudo A., Karasuyama H., Kikuchi Y., Melchers F. Long-term proliferating early pre B cell lines and clones with the potential to develop to surface Ig-positive, mitogen reactive B cells in vitro and in vivo. EMBO J. 1991 Feb;10(2):327–336. doi: 10.1002/j.1460-2075.1991.tb07953.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sakaguchi N., Kashiwamura S., Kimoto M., Thalmann P., Melchers F. B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties. EMBO J. 1988 Nov;7(11):3457–3464. doi: 10.1002/j.1460-2075.1988.tb03220.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Samaridis J., Casorati G., Traunecker A., Iglesias A., Gutierrez J. C., Müller U., Palacios R. Development of lymphocytes in interleukin 7-transgenic mice. Eur J Immunol. 1991 Feb;21(2):453–460. doi: 10.1002/eji.1830210230. [DOI] [PubMed] [Google Scholar]
  39. Sherwood P. J., Weissman I. L. The growth factor IL-7 induces expression of a transformation-associated antigen in normal pre-B cells. Int Immunol. 1990;2(5):399–406. doi: 10.1093/intimm/2.5.399. [DOI] [PubMed] [Google Scholar]
  40. Spalding D. M., Griffin J. A. Different pathways of differentiation of pre-B cell lines are induced by dendritic cells and T cells from different lymphoid tissues. Cell. 1986 Feb 14;44(3):507–515. doi: 10.1016/0092-8674(86)90472-1. [DOI] [PubMed] [Google Scholar]
  41. Steinmetz M., Zachau H. G. Two rearranged immunoglobulin kappa light chain genes in one mouse myeloma. Nucleic Acids Res. 1980 Apr 25;8(8):1693–1707. doi: 10.1093/nar/8.8.1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sudo T., Ito M., Ogawa Y., Iizuka M., Kodama H., Kunisada T., Hayashi S., Ogawa M., Sakai K., Nishikawa S. Interleukin 7 production and function in stromal cell-dependent B cell development. J Exp Med. 1989 Jul 1;170(1):333–338. doi: 10.1084/jem.170.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Takeda S., Gillis S., Palacios R. In vitro effects of recombinant interleukin 7 on growth and differentiation of bone marrow pro-B- and pro-T-lymphocyte clones and fetal thymocyte clones. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1634–1638. doi: 10.1073/pnas.86.5.1634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tominaga A., Mita S., Kikuchi Y., Hitoshi Y., Takatsu K., Nishikawa S., Ogawa M. Establishment of IL-5-dependent early B cell lines by long-term bone marrow cultures. Growth Factors. 1989;1(2):135–146. doi: 10.3109/08977198909029123. [DOI] [PubMed] [Google Scholar]
  45. Tsubata T., Reth M. The products of pre-B cell-specific genes (lambda 5 and VpreB) and the immunoglobulin mu chain form a complex that is transported onto the cell surface. J Exp Med. 1990 Sep 1;172(3):973–976. doi: 10.1084/jem.172.3.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Uckun F. M., Ledbetter J. A. Immunobiologic differences between normal and leukemic human B-cell precursors. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8603–8607. doi: 10.1073/pnas.85.22.8603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Uckun F. M. Regulation of human B-cell ontogeny. Blood. 1990 Nov 15;76(10):1908–1923. [PubMed] [Google Scholar]
  48. Weiss A., Imboden J., Hardy K., Manger B., Terhorst C., Stobo J. The role of the T3/antigen receptor complex in T-cell activation. Annu Rev Immunol. 1986;4:593–619. doi: 10.1146/annurev.iy.04.040186.003113. [DOI] [PubMed] [Google Scholar]
  49. Whitlock C. A., Tidmarsh G. F., Muller-Sieburg C., Weissman I. L. Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neoplasia-associated molecule. Cell. 1987 Mar 27;48(6):1009–1021. doi: 10.1016/0092-8674(87)90709-4. [DOI] [PubMed] [Google Scholar]
  50. Whitlock C. A., Witte O. N. Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3608–3612. doi: 10.1073/pnas.79.11.3608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wörmann B., Gesner T. G., Mufson R. A., LeBien T. W. Proliferative effect of interleukin-3 on normal and leukemic human B cell precursors. Leukemia. 1989 Jun;3(6):399–404. [PubMed] [Google Scholar]