Ontogeny of human B1 cells

  • Yuki KageyamaEmail author
  • Naoyuki Katayama
Progress in Hematology B1cells: their ontogeny and malignant counterpart


B1 cells, which are distinct from conventional B cells, are a rare B lymphocyte subpopulation that plays a pivotal role in innate immunity. Extensive previous studies have revealed the functions and ontogeny of murine B1 cells, but the properties of human B1 cells have just begun to be uncovered over the past decade. The phenotype of human B1 cells has recently been proposed, facilitating further studies. Here, we review the latest knowledge on human B1 cells, especially their ontogeny. A previous study using xenotransplantation models showed that human hematopoietic stem cells (HSCs) derived from cord blood or adult bone marrow can produce B1 cells in vivo. A recent study by our group reported that human B1 cells in peripheral blood are derived from adult HSCs and persist for approximately 3 years in situ. These findings suggest that adult human HSCs have the ability to produce B1 cells and contribute to maintenance of the adult B1 cell pool in peripheral blood. Further understanding of human B1 cell functions and ontogeny may elucidate the pathogenesis of B cell malignancies and autoimmune diseases.


Human B1 cell Ontogeny Hematopoietic stem cell 



This work was supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENHI Grant Number 17K09923).

Compliance with ethical standards

Conflict of interest

Y. Kageyama reports grants from Astellas Pharma, Kyowa Hakko Kirin, Ono Pharmaceutical, and Takeda Pharmaceutical, outside the submitted work. N. Katayama reports personal fees from Celgene and Chugai Pharmaceutical, and grants from Astellas Pharma, Kyowa Hakko Kirin, Ono Pharmaceutical, and Takeda Pharmaceutical, outside the submitted work.


  1. 1.
    Hayakawa K, Hardy RR, Parks DR, Herzenberg LA. The "Ly-1 B" cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med. 1983;157(1):202–18.PubMedCrossRefGoogle Scholar
  2. 2.
    Sidman CL, Shultz LD, Hardy RR, Hayakawa K, Herzenberg LA. Production of immunoglobulin isotypes by Ly-1+ B cells in viable motheaten and normal mice. Science. 1986;232(4756):1423–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Hayakawa K, Hardy RR, Stall AM, Herzenberg LA, Herzenberg LA. Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. Eur J Immunol. 1986;16(10):1313–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Choi YS, Baumgarth N. Dual role for B-1a cells in immunity to influenza virus infection. J Exp Med. 2008;205(13):3053–64.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol. 2011;11(1):34–46.PubMedCrossRefGoogle Scholar
  6. 6.
    Duan B, Morel L. Role of B-1a cells in autoimmunity. Autoimmun Rev. 2006;5(6):403–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Prieto JMB, Felippe MJB. Development, phenotype, and function of non-conventional B cells. Comp Immunol Microbiol Infect Dis. 2017;54:38–44.PubMedCrossRefGoogle Scholar
  8. 8.
    Yoshimoto M, Montecino-Rodriguez E, Ferkowicz MJ, Porayette P, Shelley WC, Conway SJ, et al. Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proc Natl Acad Sci USA. 2011;108(4):1468–73.PubMedCrossRefGoogle Scholar
  9. 9.
    Kobayashi M, Shelley WC, Seo W, Vemula S, Lin Y, Liu Y, et al. Functional B-1 progenitor cells are present in the hematopoietic stem cell-deficient embryo and depend on Cbfβ for their development. Proc Natl Acad Sci USA. 2014;111(33):12151–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Montecino-Rodriguez E, Dorshkind K. B-1 B cell development in the fetus and adult. Immunity. 2012;36(1):13–211.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Beaudin AE, Forsberg EC. To B1a or not to B1a: do hematopoietic stem cells contribute to tissue-resident immune cells? Blood. 2016;128(24):2765–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hayakawa K, Hardy RR, Herzenberg LA, Herzenberg LA. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J Exp Med. 1985;161(6):1554–688.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Hardy RR, Hayakawa K. A developmental switch in B lymphopoiesis. Proc Natl Acad Sci USA. 1991;88(24):11550–4.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Montecino-Rodriguez E, Fice M, Casero D, Berent-Maoz B, Barber CL, Dorshkind K. Distinct genetic networks orchestrate the emergence of specific waves of fetal and adult B-1 and B-2 development. Immunity. 2016;45(3):527–39.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Beaudin AE, Boyer SW, Perez-Cunningham J, Hernandez GE, Derderian SC, Jujjavarapu C, et al. A transient developmental hematopoietic stem cell gives rise to innate-like B and T cells. Cell Stem Cell. 2016;19(6):768–83.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Casali P, Burastero SE, Nakamura M, Inghirami G, Notkins AL. Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to Leu-1+ B-cell subset. Science. 1987;236(4797):77–81.PubMedCrossRefGoogle Scholar
  17. 17.
    Hardy RR, Hayakawa K, Shimizu M, Yamasaki K, Kishimoto T. Rheumatoid factor secretion from human Leu-1+ B cells. Science. 1987;236(4797):81–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005;105(11):4390–8.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Dalloul A. CD5: a safeguard against autoimmunity and a shield for cancer cells. Autoimmun Rev. 2009;8(4):349–53.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Lee J, Kuchen S, Fischer R, Chang S, Lipsky PE. Identification and characterization of a human CD5+ pre-naive B cell population. J Immunol. 2009;182(7):4116–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+CD27+CD43+CD70. J Exp Med. 2011;208(1):67–80.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Covens K, Verbinnen B, Geukens N, Meyts I, Schuit F, Van Lommel L, et al. Characterization of proposed human B-1 cells reveals pre-plasmablast phenotype. Blood. 2013;121(26):5176–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Inui M, Hirota S, Hirano K, Fujii H, Sugahara-Tobinai A, Ishii T, et al. Human CD43+ B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally in healthy individuals. Int Immunol. 2015;27(7):345–55.PubMedCrossRefGoogle Scholar
  24. 24.
    Quách TD, Rodríguez-Zhurbenko N, Hopkins TJ, Guo X, Hernández AM, Li W, et al. Distinctions among circulating antibody-secreting cell populations, including B-1 cells, in human adult peripheral blood. J Immunol. 2016;196(3):1060–9.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Griffin DO, Rothstein TL. Human B1 cell frequency: isolation and analysis of human B1 cells. Front Immunol. 2012;3:122.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Hayakawa K, Hardy RR, Herzenberg LA. Peritoneal Ly-1 B cells: genetic control, autoantibody production, increased lambda light chain expression. Eur J Immunol. 1986;16(4):450–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Descatoire M, Weill JC, Reynaud CA, Weller S. A human equivalent of mouse B-1 cells? J Exp Med. 2011;208(13):2563–4.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Perez-Andres M, Grosserichter-Wagener C, Teodosio C, van Dongen JJ, Orfao A, van Zelm MC. The nature of circulating CD27+CD43+ B cells. J Exp Med. 2011;208(13):2565–6.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Haas KM, Blevins MW, High KP, Pang B, Swords WE, Yammani RD. Aging promotes B-1b cell responses to native, but not protein-conjugated, pneumococcal polysaccharides: implications for vaccine protection in older adults. J Infect Dis. 2014;209(1):87–97.PubMedCrossRefGoogle Scholar
  30. 30.
    Rodriguez-Zhurbenko N, Quach TD, Hopkins TJ, Rothstein TL, Hernandez AM. Human B-1 cells and B-1 cell antibodies change with advancing age. Front Immunol. 2019;10:483.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bueno C, van Roon EH, Munoz-Lopez A, Sanjuan-Pla A, Juan M, Navarro A, et al. Immunophenotypic analysis and quantification of B-1 and B-2 B cells during human fetal hematopoietic development. Leukemia. 2016;30(7):1603–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Quách TD, Hopkins TJ, Holodick NE, Vuyyuru R, Manser T, Bayer RL, et al. Human B-1 and B-2 B cells develop from Lin–CD34+CD38lo stem cells. J Immunol. 2016;197(10):3950–8.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Moins-Teisserenc H, Busson M, Herda A, Apete S, Peffault de Latour R, Robin M, et al. CD19+CD5+ B cells and B1-like cells following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(6):988–91.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Sawai CM, Babovic S, Upadhaya S, Knapp D, Lavin Y, Lau CM, et al. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity. 2016;45(3):597–609.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Kageyama Y, Miwa H, Tawara I, Ohishi K, Masuya M, Katayama N. A population of CD20+CD27+CD43+CD38lo/int B1 cells in PNH are missing GPI-anchored proteins and harbor PIGA mutations. Blood. 2019;134(1):89–92.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Rothstein TL, Griffin DO, Holodick NE, Quach TD, Kaku H. Human B-1 cells take the stage. Ann NY Acad Sci. 2013;1285:97–114.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Cho EK, Heo DS, Seol JG, Seo EJ, Chi HS, Kim ES, et al. Ontogeny of natural killer cells and T cells by analysis of BCR–ABL rearrangement from patients with chronic myelogenous leukaemia. Br J Haematol. 2000;111(1):216–22.PubMedCrossRefGoogle Scholar
  38. 38.
    Takahashi N, Miura I, Saitoh K, Miura AB. Lineage involvement of stem cells bearing the philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood. 1998;92(12):4758–63.PubMedCrossRefGoogle Scholar
  39. 39.
    Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia. 2003;17(12):2318–57.PubMedCrossRefGoogle Scholar
  40. 40.
    Griffin DO, Rothstein TL. A small CD11b+ human B1 cell subpopulation stimulates T cells and is expanded in lupus. J Exp Med. 2011;208(13):2591–8.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Sperling S, Fiedler P, Lechner M, Pollithy A, Ehrenberg S, Schiefer AI, et al. Chronic CD30 signaling in B cells results in lymphomagenesis by driving the expansion of plasmablasts and B1 cells. Blood. 2019;133(24):2597–609.PubMedCrossRefGoogle Scholar
  42. 42.
    Yin M, Chung YJ, Lindsley RC, Walker RL, Zhu YJ, Ebert BL, et al. Engineered Bcor mutations lead to acute leukemia of progenitor B-1 lymphocyte origin in a sensitized background. Blood. 2019;133(24):2610–4.PubMedCrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Department of Hematology and OncologyMie University Graduate School of MedicineTsuJapan

Personalised recommendations