Innate B Cells: the Archetype of Protective Immune Cells

  • Alexis Grasseau
  • Marina Boudigou
  • Laëtitia Le Pottier
  • Nedra Chriti
  • Divi Cornec
  • Jacques-Olivier Pers
  • Yves Renaudineau
  • Sophie HillionEmail author


The innate B cell (IBC) population is heterogeneous and involved in the primary immune response. IBC functions include a high ability to produce natural antibodies with IgM isotype, the elimination of apoptotic cells, and a capacity to be cognate help to T cells. Among IBC subsets, B-1 cells and marginal zone B cells are the main producers of IgM, act as rapid immune responders that may relocate to follicular lymphoid and differentiate to cytokine and antibody-secreting cells shortly after infection. IBCs functions are highly dependent on their localization site and the nature of their B cell receptor repertoire, suggesting a high plasticity range of different immune responses. In this review, we will describe the nature and functions of the different innate-like B cell subsets, first in mice and then in humans. Besides this, we will emphasize the strong ability of these cells to undertake different protective functions from the first line of defense against pathogens to the regulatory role of the broader immune response.


Innate B cells Effector functions IgM Autoreactivity Regulatory B cells 



We are thankful to Dr. Wesley H. Brooks (University of South Florida, USA) for editorial assistance and to Simone Forest and Genevieve Michel for secretarial assistance.


All authors work in a department supported by the Brest University, CHU Brest, and INSERM.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

Ethical approval is not applicable as this is a review article.

Informed Consent

Informed consent is not applicable as this is a review article.


  1. 1.
    Pancer Z, Amemiya CT, Ehrhardt GR et al (2004) Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430:174–180CrossRefPubMedGoogle Scholar
  2. 2.
    Herrin BR, Alder MN, Roux KH, Sina C, Ehrhardt GRA, Boydston JA, Turnbough CL, Cooper MD (2008) Structure and specificity of lamprey monoclonal antibodies. Proc Natl Acad Sci U S A 105:2040–2045CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Li J, Barreda DR, Zhang YA, Boshra H, Gelman AE, LaPatra S, Tort L, Sunyer JO (2006) B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities. Nat Immunol 7:1116–1124CrossRefPubMedGoogle Scholar
  4. 4.
    Parra D, Rieger AM, Li J, Zhang YA, Randall LM, Hunter CA, Barreda DR, Sunyer JO (2012) Pivotal advance: peritoneal cavity B-1 B cells have phagocytic and microbicidal capacities and present phagocytosed antigen to CD4+ T cells. J Leukoc Biol 91:525–536CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bendelac A, Bonneville M, Kearney JF (2001) Autoreactivity by design: innate B and T lymphocytes. Nat Rev Immunol 1:177–186CrossRefPubMedGoogle Scholar
  6. 6.
    Gu H, Tarlinton D, Muller W, Rajewsky K, Forster I (1991) Most peripheral B cells in mice are ligand selected. J Exp Med 173:1357–1371CrossRefPubMedGoogle Scholar
  7. 7.
    Shaw PX, Horkko S, Chang MK et al (2000) Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 105:1731–1740CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pape KA, Maul RW, Dileepan T, Paustian AS, Gearhart PJ, Jenkins MK (2018) Naive B cells with high-avidity germline-encoded antigen receptors produce persistent IgM(+) and transient IgG(+) memory B cells. Immunity 48:1135–1143 e1134 CrossRefPubMedGoogle Scholar
  9. 9.
    Raposo B, Dobritzsch D, Ge C, Ekman D, Xu B, Lindh I, Förster M, Uysal H, Nandakumar KS, Schneider G, Holmdahl R (2014) Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms. J Exp Med 211:405–411CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mullazehi M, Mathsson L, Lampa J, Ronnelid J (2007) High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset. Ann Rheum Dis 66:537–541CrossRefPubMedGoogle Scholar
  11. 11.
    Cao D, Khmaladze I, Jia H, Bajtner E, Nandakumar KS, Blom T, Mo JA, Holmdahl R (2011) Pathogenic autoreactive B cells are not negatively selected toward matrix protein collagen II. J Immunol 187:4451–4458CrossRefPubMedGoogle Scholar
  12. 12.
    Hayakawa K, Asano M, Shinton SA, Gui M, Allman D, Stewart CL, Silver J, Hardy RR (1999) Positive selection of natural autoreactive B cells. Science 285:113–116CrossRefPubMedGoogle Scholar
  13. 13.
    Lam WW, Lam TP, Saing H, Chan FL, Chan KL (1999) MR cholangiography and CT cholangiography of pediatric patients with choledochal cysts. AJR Am J Roentgenol 173:401–405CrossRefPubMedGoogle Scholar
  14. 14.
    Tatu C, Ye J, Arnold LW, Clarke SH (1999) Selection at multiple checkpoints focuses V(H)12 B cell differentiation toward a single B-1 cell specificity. J Exp Med 190:903–914CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Martin F, Kearney JF (2000) Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 12:39–49CrossRefPubMedGoogle Scholar
  16. 16.
    Brink R, Phan TG (2018) Self-reactive B cells in the germinal center reaction. Annu Rev Immunol 36:339–357CrossRefPubMedGoogle Scholar
  17. 17.
    Degn SE, van der Poel CE, Firl DJ, Ayoglu B, al Qureshah FA, Bajic G, Mesin L, Reynaud CA, Weill JC, Utz PJ, Victora GD, Carroll MC (2017) Clonal evolution of autoreactive germinal centers. Cell 170:913–926 e919 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Chumley MJ, Dal Porto JM, Cambier JC (2002) The unique antigen receptor signaling phenotype of B-1 cells is influenced by locale but induced by antigen. J Immunol 169:1735–1743CrossRefPubMedGoogle Scholar
  19. 19.
    Hippen KL, Schram BR, Tze LE, Pape KA, Jenkins MK, Behrens TW (2005) In vivo assessment of the relative contributions of deletion, anergy, and editing to B cell self-tolerance. J Immunol 175:909–916CrossRefPubMedGoogle Scholar
  20. 20.
    Choi YS, Baumgarth N (2008) Dual role for B-1a cells in immunity to influenza virus infection. J Exp Med 205:3053–3064CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cerutti A, Cols M, Puga I (2013) Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 13:118–132CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ha SA, Tsuji M, Suzuki K, Meek B, Yasuda N, Kaisho T, Fagarasan S (2006) Regulation of B1 cell migration by signals through Toll-like receptors. J Exp Med 203:2541–2550CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Schneider K, Loewendorf A, De Trez C et al (2008) Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 3:67–76CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Stoermann B, Kretschmer K, Duber S, Weiss S (2007) B-1a cells are imprinted by the microenvironment in spleen and peritoneum. Eur J Immunol 37:1613–1620CrossRefPubMedGoogle Scholar
  25. 25.
    Waffarn EE, Hastey CJ, Dixit N, Soo Choi Y, Cherry S, Kalinke U, Simon SI, Baumgarth N (2015) Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation. Nat Commun 6:8991CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ravichandran KS, Lorenz U (2007) Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 7:964–974CrossRefPubMedGoogle Scholar
  27. 27.
    Chen Y, Khanna S, Goodyear CS, Park YB, Raz E, Thiel S, Gronwall C, Vas J, Boyle DL, Corr M, Kono DH, Silverman GJ (2009) Regulation of dendritic cells and macrophages by an anti-apoptotic cell natural antibody that suppresses TLR responses and inhibits inflammatory arthritis. J Immunol 183:1346–1359CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ogden CA, Kowalewski R, Peng Y, Montenegro V, Elkon KB (2005) IGM is required for efficient complement mediated phagocytosis of apoptotic cells in vivo. Autoimmunity 38:259–264CrossRefPubMedGoogle Scholar
  29. 29.
    Miles K, Simpson J, Brown S et al (2017) Immune tolerance to apoptotic self is mediated primarily by regulatory B1a cells. Front Immunol 8:1952CrossRefPubMedGoogle Scholar
  30. 30.
    Nguyen TT, Elsner RA, Baumgarth N (2015) Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction. J Immunol 194:1489–1502CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Holodick NE, Tumang JR, Rothstein TL (2009) Continual signaling is responsible for constitutive ERK phosphorylation in B-1a cells. Mol Immunol 46:3029–3036CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Gil-Cruz C, Bobat S, Marshall JL, Kingsley RA, Ross EA, Henderson IR, Leyton DL, Coughlan RE, Khan M, Jensen KT, Buckley CD, Dougan G, MacLennan ICM, Lopez-Macias C, Cunningham AF (2009) The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response. Proc Natl Acad Sci U S A 106:9803–9808CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Savage HP, Yenson VM, Sawhney SS, Mousseau BJ, Lund FE, Baumgarth N (2017) Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells. J Exp Med 214:2777–2794CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF (2008) A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28:639–650CrossRefPubMedGoogle Scholar
  35. 35.
    Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, Simon Q, Thalmensi J, Baures A, Flühler V, Sakwa I, Stervbo U, Ries S, Jouneau L, Boudinot P, Tsubata T, Adachi T, Hutloff A, Dörner T, Zimber-Strobl U, de Vos AF, Dahlke K, Loh G, Korniotis S, Goosmann C, Weill JC, Reynaud CA, Kaufmann SHE, Walter J, Fillatreau S (2018) LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells. Immunity 49:120–133 e129 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Racine R, Chatterjee M, Winslow GM (2008) CD11c expression identifies a population of extrafollicular antigen-specific splenic plasmablasts responsible for CD4 T-independent antibody responses during intracellular bacterial infection. J Immunol 181:1375–1385CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Winslow GM, Papillion AM, Kenderes KJ, Levack RC (2017) CD11c+ T-bet+ memory B cells: immune maintenance during chronic infection and inflammation? Cell Immunol 321:8–17CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Yates JL, Racine R, McBride KM, Winslow GM (2013) T cell-dependent IgM memory B cells generated during bacterial infection are required for IgG responses to antigen challenge. J Immunol 191:1240–1249CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Racine R, Jones DD, Chatterjee M, McLaughlin M, MacNamara KC, Winslow GM (2010) Impaired germinal center responses and suppression of local IgG production during intracellular bacterial infection. J Immunol 184:5085–5093CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Rubtsov AV, Rubtsova K, Kappler JW, Jacobelli J, Friedman RS, Marrack P (2015) CD11c-expressing B cells are located at the T cell/B cell border in spleen and are potent APCs. J Immunol 195:71–79CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Rubtsova K, Rubtsov AV, Thurman JM, Mennona JM, Kappler JW, Marrack P (2017) B cells expressing the transcription factor T-bet drive lupus-like autoimmunity. J Clin Invest 127:1392–1404CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wang S, Wang J, Kumar V et al (2018) IL-21 drives expansion and plasma cell differentiation of autoreactive CD11c(hi)T-bet(+) B cells in SLE. Nat Commun 9:1758CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Shi W, Liao Y, Willis SN, Taubenheim N, Inouye M, Tarlinton DM, Smyth GK, Hodgkin PD, Nutt SL, Corcoran LM (2015) Transcriptional profiling of mouse B cell terminal differentiation defines a signature for antibody-secreting plasma cells. Nat Immunol 16:663–673CrossRefPubMedGoogle Scholar
  44. 44.
    Chorny A, Casas-Recasens S, Sintes J, Shan M, Polentarutti N, García-Escudero R, Walland AC, Yeiser JR, Cassis L, Carrillo J, Puga I, Cunha C, Bastos H, Rodrigues F, Lacerda JF, Morais A, Dieguez-Gonzalez R, Heeger PS, Salvatori G, Carvalho A, Garcia-Sastre A, Blander JM, Mantovani A, Garlanda C, Cerutti A (2017) Correction: the soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells. J Exp Med 214:1559CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sintes J, Gentile M, Zhang S, Garcia-Carmona Y, Magri G, Cassis L, Segura-Garzón D, Ciociola A, Grasset EK, Bascones S, Comerma L, Pybus M, Lligé D, Puga I, Gutzeit C, He B, DuBois W, Crespo M, Pascual J, Mensa A, Aróstegui JI, Juan M, Yagüe J, Serrano S, Lloreta J, Meffre E, Hahne M, Cunningham-Rundles C, Mock BA, Cerutti A (2017) mTOR intersects antibody-inducing signals from TACI in marginal zone B cells. Nat Commun 8:1462CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Attanavanich K, Kearney JF (2004) Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J Immunol 172:803–811CrossRefPubMedGoogle Scholar
  47. 47.
    Cinamon G, Zachariah MA, Lam OM, Foss FW Jr, Cyster JG (2008) Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol 9:54–62CrossRefPubMedGoogle Scholar
  48. 48.
    Lu TT, Cyster JG (2002) Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297:409–412CrossRefPubMedGoogle Scholar
  49. 49.
    Song H, Cerny J (2003) Functional heterogeneity of marginal zone B cells revealed by their ability to generate both early antibody-forming cells and germinal centers with hypermutation and memory in response to a T-dependent antigen. J Exp Med 198:1923–1935CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Chappell CP, Draves KE, Giltiay NV, Clark EA (2012) Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med 209:1825–1840CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Puga I, Cols M, Barra CM et al (2011) B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13:170, 2012Google Scholar
  52. 52.
    Kleiman E, Salyakina D, De Heusch M et al (2015) Distinct transcriptomic features are associated with transitional and mature B-cell populations in the mouse spleen. Front Immunol 6:30CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Barral P, Eckl-Dorna J, Harwood NE, de Santo C, Salio M, Illarionov P, Besra GS, Cerundolo V, Batista FD (2008) B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc Natl Acad Sci U S A 105:8345–8350CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Batista FD, Harwood NE (2009) The who, how and where of antigen presentation to B cells. Nat Rev Immunol 9:15–27CrossRefPubMedGoogle Scholar
  55. 55.
    Gaya M, Barral P, Burbage M, Aggarwal S, Montaner B, Warren Navia A, Aid M, Tsui C, Maldonado P, Nair U, Ghneim K, Fallon PG, Sekaly RP, Barouch DH, Shalek AK, Bruckbauer A, Strid J, Batista FD (2018) Initiation of antiviral B cell immunity relies on innate signals from spatially positioned NKT cells. Cell 172:517–533 e520CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Magri G, Miyajima M, Bascones S, Mortha A, Puga I, Cassis L, Barra CM, Comerma L, Chudnovskiy A, Gentile M, Llige D, Cols M, Serrano S, Aróstegui JI, Juan M, Yagüe J, Merad M, Fagarasan S, Cerutti A (2014) Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol 15:354–364CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Wolf SD, Dittel BN, Hardardottir F, Janeway CA, Jr. (1996) Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 184:2271–2278Google Scholar
  58. 58.
    Zhang X, Deriaud E, Jiao X, Braun D, Leclerc C, Lo-Man R (2007) Type I interferons protect neonates from acute inflammation through interleukin 10-producing B cells. J Exp Med 204:1107–1118CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Gonzalez-Garcia I, Ocana E, Jimenez-Gomez G, Campos-Caro A, Brieva JA (2006) Immunization-induced perturbation of human blood plasma cell pool: progressive maturation, IL-6 responsiveness, and high PRDI-BF1/BLIMP1 expression are critical distinctions between antigen-specific and nonspecific plasma cells. J Immunol 176:4042–4050CrossRefPubMedGoogle Scholar
  60. 60.
    Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN, Fallon PG (2004) Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol 173:6346–6356CrossRefPubMedGoogle Scholar
  61. 61.
    Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG (2010) Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. J Allergy Clin Immunol 125:1114–1124 e1118 CrossRefPubMedGoogle Scholar
  62. 62.
    Velupillai P, Harn DA (1994) Oligosaccharide-specific induction of interleukin 10 production by B220+ cells from schistosome-infected mice: a mechanism for regulation of CD4+ T-cell subsets. Proc Natl Acad Sci U S A 91:18–22CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Ronet C, Hauyon-La Torre Y, Revaz-Breton M et al (2010) Regulatory B cells shape the development of Th2 immune responses in BALB/c mice infected with Leishmania major through IL-10 production. J Immunol 184:886–894CrossRefPubMedGoogle Scholar
  64. 64.
    Di Niro R, Lee SJ, Vander Heiden JA et al (2015) Salmonella infection drives promiscuous B cell activation followed by Extrafollicular affinity maturation. Immunity 43:120–131CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Salazar GA, Penaloza HF, Pardo-Roa C et al (2017) Interleukin-10 production by T and B cells is a key factor to promote systemic Salmonella enterica serovar Typhimurium infection in mice. Front Immunol 8:889CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Neves P, Lampropoulou V, Calderon-Gomez E, Roch T, Stervbo U, Shen P, Kühl AA, Loddenkemper C, Haury M, Nedospasov SA, Kaufmann SHE, Steinhoff U, Calado DP, Fillatreau S (2010) Signaling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity 33:777–790CrossRefPubMedGoogle Scholar
  67. 67.
    Seibert SA, Mex P, Kohler A, Kaufmann SH, Mittrucker HW (2010) TLR2-, TLR4- and Myd88-independent acquired humoral and cellular immunity against Salmonella enterica serovar Typhimurium. Immunol Lett 127:126–134CrossRefPubMedGoogle Scholar
  68. 68.
    Shen P, Roch T, Lampropoulou V, O’Connor RA, Stervbo U, Hilgenberg E, Ries S, Dang VD, Jaimes Y, Daridon C, Li R, Jouneau L, Boudinot P, Wilantri S, Sakwa I, Miyazaki Y, Leech MD, McPherson RC, Wirtz S, Neurath M, Hoehlig K, Meinl E, Grützkau A, Grün JR, Horn K, Kühl AA, Dörner T, Bar-Or A, Kaufmann SHE, Anderton SM, Fillatreau S (2014) IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507:366–370CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Buendia AJ, Del Rio L, Ortega N et al (2002) B-cell-deficient mice show an exacerbated inflammatory response in a model of Chlamydophila abortus infection. Infect Immun 70:6911–6918CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Madan R, Demircik F, Surianarayanan S, Allen JL, Divanovic S, Trompette A, Yogev N, Gu Y, Khodoun M, Hildeman D, Boespflug N, Fogolin MB, Grobe L, Greweling M, Finkelman FD, Cardin R, Mohrs M, Muller W, Waisman A, Roers A, Karp CL (2009) Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J Immunol 183:2312–2320CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Goenka R, Parent MA, Elzer PH, Baldwin CL (2011) B cell-deficient mice display markedly enhanced resistance to the intracellular bacterium Brucella abortus. J Infect Dis 203:1136–1146CrossRefPubMedGoogle Scholar
  72. 72.
    Das A, Ellis G, Pallant C, Lopes AR, Khanna P, Peppa D, Chen A, Blair P, Dusheiko G, Gill U, Kennedy PT, Brunetto M, Lampertico P, Mauri C, Maini MK (2012) IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol 189:3925–3935CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Liu J, Zhan W, Kim CJ, Clayton K, Zhao H, Lee E, Cao JC, Ziegler B, Gregor A, Yue FY, Huibner S, MacParland S, Schwartz J, Song HH, Benko E, Gyenes G, Kovacs C, Kaul R, Ostrowski M (2014) IL-10-producing B cells are induced early in HIV-1 infection and suppress HIV-1-specific T cell responses. PLoS One 9:e89236CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Yosef N, Regev A (2016) Writ large: genomic dissection of the effect of cellular environment on immune response. Science 354:64–68CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Xie H, Ye M, Feng R, Graf T (2004) Stepwise reprogramming of B cells into macrophages. Cell 117:663–676CrossRefPubMedGoogle Scholar
  76. 76.
    Barneda-Zahonero B, Roman-Gonzalez L, Collazo O et al (2013) HDAC7 is a repressor of myeloid genes whose downregulation is required for transdifferentiation of pre-B cells into macrophages. PLoS Genet 9:e1003503CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Cirovic B, Schonheit J, Kowenz-Leutz E et al (2017) C/EBP-induced transdifferentiation reveals granulocyte-macrophage precursor-like plasticity of B cells. Stem Cell Reports 8:346–359CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Audzevich T, Bashford-Rogers R, Mabbott NA, Frampton D, Freeman TC, Potocnik A, Kellam P, Gilroy DW (2017) Pre/pro-B cells generate macrophage populations during homeostasis and inflammation. Proc Natl Acad Sci U S A 114:E3954–E3963CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Zhang M, Dong Y, Hu F et al (2018) Publisher correction: transcription factor Hoxb5 reprograms B cells into functional T lymphocytes. Nat Immunol In Press Google Scholar
  80. 80.
    Johnson BA 3rd, Kahler DJ, Baban B et al (2010) B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 107:10644–10648CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Wang S, Xia P, Chen Y, Huang G, Xiong Z, Liu J, Li C, Ye B, du Y, Fan Z (2016) Natural killer-like B cells prime innate lymphocytes against microbial infection. Immunity 45:131–144CrossRefPubMedGoogle Scholar
  82. 82.
    Kerdiles YM, Almeida FF, Thompson T, Chopin M, Vienne M, Bruhns P, Huntington ND, Raulet DH, Nutt SL, Belz GT, Vivier E (2017) Natural-killer-like B cells display the phenotypic and functional characteristics of conventional B cells. Immunity 47:199–200CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Topalian SL (2017) Targeting immune checkpoints in cancer therapy. JAMA 318:1647–1648CrossRefPubMedGoogle Scholar
  85. 85.
    van der Vlist M, Kuball J, Radstake TR, Meyaard L (2016) Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat Rev Rheumatol 12:593–604CrossRefPubMedGoogle Scholar
  86. 86.
    Steiniger B, Timphus EM, Barth PJ (2006) The splenic marginal zone in humans and rodents: an enigmatic compartment and its inhabitants. Histochem Cell Biol 126:641–648CrossRefPubMedGoogle Scholar
  87. 87.
    Griffin DO, Holodick NE, Rothstein TL (2011) Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70. J Exp Med 208:67–80CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Hardy RR, Carmack CE, Shinton SA, Riblet RJ, Hayakawa K (1989) A single VH gene is utilized predominantly in anti-BrMRBC hybridomas derived from purified Ly-1 B cells. Definition of the VH11 family. J Immunol 142:3643–3651PubMedGoogle Scholar
  89. 89.
    Lalor PA, Morahan G (1990) The peritoneal Ly-1 (CD5) B cell repertoire is unique among murine B cell repertoires. Eur J Immunol 20:485–492CrossRefPubMedGoogle Scholar
  90. 90.
    Mageed RA, Garaud S, Taher TE, Parikh K, Pers JO, Jamin C, Renaudineau Y, Youinou P (2012) CD5 expression promotes multiple intracellular signaling pathways in B lymphocyte. Autoimmun Rev 11:795–798CrossRefPubMedGoogle Scholar
  91. 91.
    Renaudineau Y, Hillion S, Saraux A, Mageed RA, Youinou P (2005) An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes. Blood 106:2781–2789CrossRefPubMedGoogle Scholar
  92. 92.
    Descatoire M, Weill JC, Reynaud CA, Weller S (2011) A human equivalent of mouse B-1 cells? J Exp Med 208:2563–2564CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Perez-Andres M, Grosserichter-Wagener C, Teodosio C, van Dongen JJM, Orfao A, van Zelm MC (2011) The nature of circulating CD27+CD43+ B cells. J Exp Med 208:2565–2566CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Huang B, Faucette AN, Pawlitz MD, Pei B, Goyert JW, Zhou JZ, el-Hage NG, Deng J, Lin J, Yao F, Dewar RS, Jassal JS, Sandberg ML, Dai J, Cols M, Shen C, Polin LA, Nichols RA, Jones TB, Bluth MH, Puder KS, Gonik B, Nayak NR, Puscheck E, Wei WZ, Cerutti A, Colonna M, Chen K (2017) Interleukin-33-induced expression of PIBF1 by decidual B cells protects against preterm labor. Nat Med 23:128–135CrossRefPubMedGoogle Scholar
  95. 95.
    Jensen F, Wallukat G, Herse F, Budner O, el-Mousleh T, Costa SD, Dechend R, Zenclussen AC (2012) CD19+CD5+ cells as indicators of preeclampsia. Hypertension 59:861–868CrossRefPubMedGoogle Scholar
  96. 96.
    Mebius RE, Nolte MA, Kraal G (2004) Development and function of the splenic marginal zone. Crit Rev Immunol 24:449–464CrossRefPubMedGoogle Scholar
  97. 97.
    Dunn-Walters DK, Isaacson PG, Spencer J (1995) Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J Exp Med 182:559–566CrossRefPubMedGoogle Scholar
  98. 98.
    Klein U, Kuppers R, Rajewsky K (1997) Evidence for a large compartment of IgM-expressing memory B cells in humans. Blood 89:1288–1298PubMedGoogle Scholar
  99. 99.
    Weller S, Braun MC, Tan BK, Rosenwald A, Cordier C, Conley ME, Plebani A, Kumararatne DS, Bonnet D, Tournilhac O, Tchernia G, Steiniger B, Staudt LM, Casanova JL, Reynaud CA, Weill JC (2004) Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 104:3647–3654CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Weller S, Mamani-Matsuda M, Picard C, Cordier C, Lecoeuche D, Gauthier F, Weill JC, Reynaud CA (2008) Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+ IgD+ CD27+ B cell repertoire in infants. J Exp Med 205:1331–1342CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Weller S, Faili A, Garcia C, Braun MC, le Deist F, de Saint Basile G, Hermine O, Fischer A, Reynaud CA, Weill JC (2001) CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. Proc Natl Acad Sci U S A 98:1166–1170CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Tangye SG, Good KL (2007) Human IgM+CD27+ B cells: memory B cells or "memory" B cells? J Immunol 179:13–19CrossRefPubMedGoogle Scholar
  103. 103.
    Seifert M, Przekopowitz M, Taudien S, Lollies A, Ronge V, Drees B, Lindemann M, Hillen U, Engler H, Singer BB, Küppers R (2015) Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions. Proc Natl Acad Sci U S A 112:E546–E555CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Bagnara D, Squillario M, Kipling D, Mora T, Walczak AM, da Silva L, Weller S, Dunn-Walters DK, Weill JC, Reynaud CA (2015) A reassessment of IgM memory subsets in humans. J Immunol 195:3716–3724CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Martin V, Wu YC, Kipling D, Dunn-Walters DK (2015) Age-related aspects of human IgM(+) B cell heterogeneity. Ann N Y Acad Sci 1362:153–163CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Cornec D, Berti A, Hummel A, Peikert T, Pers JO, Specks U (2017) Identification and phenotyping of circulating autoreactive proteinase 3-specific B cells in patients with PR3-ANCA associated vasculitis and healthy controls. J Autoimmun 84:122–131CrossRefPubMedGoogle Scholar
  107. 107.
    Gazeau P, Alegria GC, Devauchelle-Pensec V, Jamin C, Lemerle J, Bendaoud B, Brooks WH, Saraux A, Cornec D, Renaudineau Y (2017) Memory B cells and response to abatacept in rheumatoid arthritis. Clin Rev Allergy Immunol 53:166–176CrossRefPubMedGoogle Scholar
  108. 108.
    Carvajal Alegria G, Gazeau P, Hillion S, Daien CI, Cornec DYK (2017) Could lymphocyte profiling be useful to diagnose systemic autoimmune diseases? Clin Rev Allergy Immunol 53:219–236CrossRefPubMedGoogle Scholar
  109. 109.
    Rodriguez-Bayona B, Ramos-Amaya A, Perez-Venegas JJ, Rodriguez C, Brieva JA (2010) Decreased frequency and activated phenotype of blood CD27 IgD IgM B lymphocytes is a permanent abnormality in systemic lupus erythematosus patients. Arthritis Res Ther 12:R108CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, Tomar D, Woodruff MC, Simon Z, Bugrovsky R, Blalock EL, Scharer CD, Tipton CM, Wei C, Lim SS, Petri M, Niewold TB, Anolik JH, Gibson G, Lee FEH, Boss JM, Lund FE, Sanz I (2018) Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity 49:725–739 e726CrossRefPubMedGoogle Scholar
  111. 111.
    Simonin L, Pasquier E, Leroyer C, Cornec D, Lemerle J, Bendaoud B, Hillion S, Pers JO, Couturaud F, Renaudineau Y (2017) Lymphocyte disturbances in primary antiphospholipid syndrome and application to venous thromboembolism follow-up. Clin Rev Allergy Immunol 53:14–27CrossRefPubMedGoogle Scholar
  112. 112.
    Ichikawa D, Asano M, Shinton SA, Brill-Dashoff J, Formica AM, Velcich A, Hardy RR, Hayakawa K (2015) Natural anti-intestinal goblet cell autoantibody production from marginal zone B cells. J Immunol 194:606–614CrossRefPubMedGoogle Scholar
  113. 113.
    Tangye SG, Liu YJ, Aversa G, Phillips JH, de Vries JE (1998) Identification of functional human splenic memory B cells by expression of CD148 and CD27. J Exp Med 188:1691–1703CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Descatoire M, Weller S, Irtan S, Sarnacki S, Feuillard J, Storck S, Guiochon-Mantel A, Bouligand J, Morali A, Cohen J, Jacquemin E, Iascone M, Bole-Feysot C, Cagnard N, Weill JC, Reynaud CA (2014) Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties. J Exp Med 211:987–1000CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Zhao Y, Uduman M, Siu JHY, Tull TJ, Sanderson JD, Wu YCB, Zhou JQ, Petrov N, Ellis R, Todd K, Chavele KM, Guesdon W, Vossenkamper A, Jassem W, D’Cruz DP, Fear DJ, John S, Scheel-Toellner D, Hopkins C, Moreno E, Woodman NL, Ciccarelli F, Heck S, Kleinstein SH, Bemark M, Spencer J (2018) Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue. Nat Commun 9:3857CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Fasnacht N, Huang HY, Koch U, Favre S, Auderset F, Chai Q, onder L, Kallert S, Pinschewer DD, MacDonald HR, Tacchini-Cottier F, Ludewig B, Luther SA, Radtke F (2014) Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. J Exp Med 211:2265–2279CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Hammad H, Vanderkerken M, Pouliot P, Deswarte K, Toussaint W, Vergote K, Vandersarren L, Janssens S, Ramou I, Savvides SN, Haigh JJ, Hendriks R, Kopf M, Craessaerts K, de Strooper B, Kearney JF, Conrad DH, Lambrecht BN (2017) Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10. Nat Immunol 18:313–320CrossRefPubMedGoogle Scholar
  118. 118.
    Magri G, Comerma L, Pybus M, Sintes J, Lligé D, Segura-Garzón D, Bascones S, Yeste A, Grasset EK, Gutzeit C, Uzzan M, Ramanujam M, van Zelm MC, Albero-González R, Vazquez I, Iglesias M, Serrano S, Márquez L, Mercade E, Mehandru S, Cerutti A (2017) Human secretory IgM emerges from plasma cells clonally related to gut memory B cells and targets highly diverse commensals. Immunity 47:118–134 e118 CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Simon Q, Pers JO, Cornec D, le Pottier L, Mageed RA, Hillion S (2016) In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles. J Allergy Clin Immunol 137:1577–1584 e1510 CrossRefPubMedGoogle Scholar
  120. 120.
    Blair PA, Norena LY, Flores-Borja F et al (2010) CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32:129–140CrossRefPubMedGoogle Scholar
  121. 121.
    Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM (2005) Lyn tyrosine kinase: accentuating the positive and the negative. Immunity 22:9–18PubMedGoogle Scholar
  122. 122.
    Berkowska MA, Driessen GJ, Bikos V et al (2011) Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways. Blood 118:2150–2158CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Bouaziz JD, Calbo S, Maho-Vaillant M, Saussine A, Bagot M, Bensussan A, Musette P (2010) IL-10 produced by activated human B cells regulates CD4(+) T-cell activation in vitro. Eur J Immunol 40:2686–2691CrossRefPubMedGoogle Scholar
  124. 124.
    Iwata Y, Matsushita T, Horikawa M, DiLillo DJ, Yanaba K, Venturi GM, Szabolcs PM, Bernstein SH, Magro CM, Williams AD, Hall RP, St Clair EW, Tedder TF (2011) Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117:530–541CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Lemoine S, Morva A, Youinou P, Jamin C (2011) Human T cells induce their own regulation through activation of B cells. J Autoimmun 36:228–238CrossRefPubMedGoogle Scholar
  126. 126.
    Nouel A, Segalen I, Jamin C et al (2014) B cells display an abnormal distribution and an impaired suppressive function in patients with chronic antibody-mediated rejection. Kidney Int 85:590–599CrossRefPubMedGoogle Scholar
  127. 127.
    Siewe B, Stapleton JT, Martinson J, Keshavarzian A, Kazmi N, Demarais PM, French AL, Landay A (2013) Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8(+) T cell function in vitro. J Leukoc Biol 93:811–818CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Chagnon-Choquet J, Fontaine J, Poudrier J, Roger M, for the Montreal Primary HIV Infection and Slow Progressor Study Groups (2014) IL-10 and lymphotoxin-alpha expression profiles within marginal zone-like B-cell populations are associated with control of HIV-1 disease progression. PLoS One 9:e101949Google Scholar
  129. 129.
    de Masson A, Bouaziz JD, Le Buanec H et al (2015) CD24(hi)CD27(+) and plasmablast-like regulatory B cells in human chronic graft-versus-host disease. Blood 125:1830–1839CrossRefPubMedGoogle Scholar
  130. 130.
    Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, Kallies A, Nutt SL, Sakaguchi S, Takeda K, Kurosaki T, Baba Y (2014) Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 41:1040–1051CrossRefPubMedGoogle Scholar
  131. 131.
    Ticha O, Moos L, Wajant H, Bekeredjian-Ding I (2017) Expression of tumor necrosis factor receptor 2 characterizes TLR9-driven formation of Interleukin-10-producing B cells. Front Immunol 8:1951CrossRefPubMedGoogle Scholar
  132. 132.
    Guia S, Vivier E, Narni-Mancinelli E (2019) Helper-like innate lymphoid cells: definition, functions and clinical implications in inflammatory diseases and cancer. Clin Rev Allerg Immunol. In PressGoogle Scholar
  133. 133.
    Brilland B, Scherlinger M, Khoryati L et al (2019) Platelets and IgE: shaping the innate immune response in systemic lupus erythematosus. Clin Rev Allerg Immunol. In PressGoogle Scholar
  134. 134.
    Maddur MS, Lacroix-Desmazes S, Dimitrov JD et al (2019) Natural antibodies: from first line defense against pathogens to perpetual immune homeostasis. Clin Rev Allerg Immunol. In PressGoogle Scholar
  135. 135.
    Defendia F, Thielensb NM, Clavarinoa G, Cesbron JY, Dumestre-Pérard C (2019) Autoantibodies targeting complement components and associated diseases. Clin Rev Allerg Immunol. In PressGoogle Scholar
  136. 136.
    Bordron A, Bagacean C, Tempescul A et al (2019) Complement system: a neglected pathway in immunotherapy. Clin Rev Allerg Immunol. In PressGoogle Scholar
  137. 137.
    Arleevskaya MI, Larionova RV, Brooks WH, Bettacchioli E, Renaudineau Y (2019) TLR, infections and rheumatoid arthritis. Clin Rev Allerg Immunol. In PressGoogle Scholar
  138. 138.
    Charras A, Arvaniti P, Le Dantec C et al (2019) JAK1/2 inhibitors suppress epigenetic reprogramming of two innate immune cytokines (IFNα, IFNγ) and reactive oxygen species: a promise for patients with Sjögren’s syndrome. Clin Rev Allerg Immunol. In PressGoogle Scholar
  139. 139.
    Hillion S, Arleevskaya MI, Brooks WH et al (2019) The innate part of the adaptive immube system. Clin Rev Allerg Immunol. In PressGoogle Scholar
  140. 140.
    Arleevskaya MI, Aminov R, Brooks WH, Manukyan G, Renaudineau Y (2019) Editorial: shaping oh human immune system and metabolic processes by viruses and microorganisms. Front Microbiol 10:816CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Alexis Grasseau
    • 1
  • Marina Boudigou
    • 1
  • Laëtitia Le Pottier
    • 1
  • Nedra Chriti
    • 1
  • Divi Cornec
    • 1
  • Jacques-Olivier Pers
    • 1
  • Yves Renaudineau
    • 1
    • 2
  • Sophie Hillion
    • 1
    • 2
    Email author
  1. 1.UMR1227, Lymphocytes B et Autoimmunité, Université de Brest, INSERMCHU de BrestBrestFrance
  2. 2.Laboratory of Immunology and ImmunotherapyCHU BrestBrestFrance

Personalised recommendations