Toll‐like receptors – sentries in the B‐cell response

Toll‐like receptors (TLR) play a central role in the initiation of the innate immune response to pathogens. Upon recognition of molecular motifs specific for microbial molecules TLR mediate pro‐inflammatory cytokine secretion and enhance antigen presentation; in B cells they further promote expansion, class switch recombination and immunoglobulin secretion. As a result of their adjuvant properties, TLR ligands have become an integral component of antimicrobial vaccines. In spite of this, little is known of the direct effects of TLR engagement on B‐lymphocyte function. The scope of this review is to outline the differences in TLR expression and reactivity in murine and human B‐cell subsets and to provide an overview of the currently available literature. We will further discuss the possible roles of TLR in regulating B‐cell effector functions and shaping antibody‐mediated defence against microbial pathogens in vivo.

[1]  A. Marshall,et al.  Role of phosphoinositide 3-kinase p110 delta in TLR4- and TLR9-mediated B cell cytokine production and differentiation. , 2009, Molecular immunology.

[2]  John Calvin Reed,et al.  Lymphocyte-specific TRAF3 transgenic mice have enhanced humoral responses and develop plasmacytosis, autoimmunity, inflammation, and cancer. , 2009, Blood.

[3]  F. Batista,et al.  BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. , 2009, Blood.

[4]  K. Riesbeck,et al.  Superantigen- and TLR-Dependent Activation of Tonsillar B Cells after Receptor-Mediated Endocytosis 1 , 2009, The Journal of Immunology.

[5]  J. Cambier,et al.  Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells , 2009, Proceedings of the National Academy of Sciences.

[6]  U. Bommhardt,et al.  TLR9-Activating DNA Up-Regulates ZAP70 via Sustained PKB Induction in IgM+ B Cells1 , 2008, The Journal of Immunology.

[7]  J. Borneman,et al.  Resident enteric microbiota and CD8+ T cells shape the abundance of marginal zone B cells , 2008, European journal of immunology.

[8]  J. Casanova,et al.  IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. , 2008, Immunity.

[9]  Y. Richard,et al.  Identification of two subpopulations of purified human blood B cells, CD27− CD23+ and CD27high CD80+, that strongly express cell surface Toll‐like receptor 9 and secrete high levels of interleukin‐6 , 2008, Immunology.

[10]  I. Cohen,et al.  Induction of IgG3 to LPS via Toll-Like Receptor 4 Co-Stimulation , 2008, PloS one.

[11]  I. Bekeredjian-Ding,et al.  Staphylococcus aureus-Induced Plasmacytoid Dendritic Cell Activation Is Based on an IgG-Mediated Memory Response1 , 2008, The Journal of Immunology.

[12]  R. Bataille,et al.  Toll-like receptors: lessons to learn from normal and malignant human B cells. , 2008, Blood.

[13]  M. Huber,et al.  Enhanced B‐cell activation mediated by TLR4 and BCR crosstalk , 2008, European journal of immunology.

[14]  S. Pierce,et al.  The Agonists of TLR4 and 9 Are Sufficient to Activate Memory B Cells to Differentiate into Plasma Cells In Vitro but Not In Vivo1 , 2008, The Journal of Immunology.

[15]  K. Miyake,et al.  TLR accessory molecules. , 2008, Current opinion in immunology.

[16]  E. Clark,et al.  Regulation of B‐cell entry into the cell cycle , 2008, Immunological reviews.

[17]  J. Vasilakos,et al.  Comparison of human B cell activation by TLR7 and TLR9 agonists , 2008, BMC Immunology.

[18]  A. Fauci,et al.  CpG Oligonucleotides Enhance Proliferative and Effector Responses of B Cells in HIV-Infected Individuals1 , 2008, The Journal of Immunology.

[19]  A. Plebani,et al.  Viral Double-Stranded RNA Triggers Ig Class Switching by Activating Upper Respiratory Mucosa B Cells through an Innate TLR3 Pathway Involving BAFF1 , 2008, The Journal of Immunology.

[20]  Michelle M. Sandau,et al.  Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation , 2008, Nature Immunology.

[21]  E. Wong,et al.  Bruton's Tyrosine Kinase Separately Regulates NFκB p65RelA Activation and Cytokine Interleukin (IL)-10/IL-12 Production in TLR9-stimulated B Cells* , 2008, Journal of Biological Chemistry.

[22]  U. Steinhoff,et al.  TLR-Activated B Cells Suppress T Cell-Mediated Autoimmunity1 , 2008, The Journal of Immunology.

[23]  D. Dorward,et al.  The B cell receptor governs the subcellular location of Toll‐like receptor 9 leading to hyper‐responses to DNA‐containing antigens , 2008, Immunity.

[24]  K. Calame,et al.  Regulation and functions of Blimp-1 in T and B lymphocytes. , 2008, Annual review of immunology.

[25]  R. Pelanda,et al.  TLR Agonists Promote Marginal Zone B Cell Activation and Facilitate T-Dependent IgM Responses1 , 2008, The Journal of Immunology.

[26]  H. Ploegh,et al.  UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes , 2008, Nature.

[27]  A. Plebani,et al.  CpG Drives Human Transitional B Cells to Terminal Differentiation and Production of Natural Antibodies , 2008, The Journal of Immunology.

[28]  J. Kearney,et al.  CD36 Is Differentially Expressed on B Cell Subsets during Development and in Responses to Antigen1 , 2008, The Journal of Immunology.

[29]  D. Rawlings,et al.  B cell–intrinsic TLR signals amplify but are not required for humoral immunity , 2007, The Journal of experimental medicine.

[30]  T. Behrens,et al.  Functional Outcome of B Cell Activation by Chromatin Immune Complex Engagement of the B Cell Receptor and TLR91 , 2007, The Journal of Immunology.

[31]  D. Gray,et al.  TLR-mediated stimulation of APC: Distinct cytokine responses of B cells and dendritic cells , 2007, European journal of immunology.

[32]  Douglas R. McDonald,et al.  Selective predisposition to bacterial infections in IRAK-4–deficient children: IRAK-4–dependent TLRs are otherwise redundant in protective immunity , 2007, The Journal of experimental medicine.

[33]  B. Pulendran,et al.  Toll-Like Receptor Expression and Responsiveness of Distinct Murine Splenic and Mucosal B-Cell Subsets , 2007, PloS one.

[34]  Jessica M. Lindvall,et al.  Defective Toll‐like receptor 9‐mediated cytokine production in B cells from Bruton's tyrosine kinase‐deficient mice , 2007, Immunology.

[35]  P. Borrow,et al.  Polyinosinic Acid Is a Ligand for Toll-like Receptor 3* , 2007, Journal of Biological Chemistry.

[36]  M. Lederman,et al.  TLR9 stimulation drives naïve B cells to proliferate and to attain enhanced antigen presenting function , 2007, European journal of immunology.

[37]  S. Gerondakis,et al.  Regulating B‐cell activation and survival in response to TLR signals , 2007, Immunology and cell biology.

[38]  P. Brandtzaeg Induction of secretory immunity and memory at mucosal surfaces. , 2007, Vaccine.

[39]  A. Krieg Antiinfective applications of toll-like receptor 9 agonists. , 2007, Proceedings of the American Thoracic Society.

[40]  B. Guy,et al.  The perfect mix: recent progress in adjuvant research , 2007, Nature Reviews Microbiology.

[41]  T. Rothstein,et al.  B Cell Receptor Cross-Talk: Exposure to Lipopolysaccharide Induces an Alternate Pathway for B Cell Receptor-Induced ERK Phosphorylation and NF-κB Activation1 , 2007, The Journal of Immunology.

[42]  A. Plebani,et al.  Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. , 2007, Immunity.

[43]  L. Genestier,et al.  TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses1 , 2007, The Journal of Immunology.

[44]  E. Milner,et al.  A New Population of Cells Lacking Expression of CD27 Represents a Notable Component of the B Cell Memory Compartment in Systemic Lupus Erythematosus1 , 2007, The Journal of Immunology.

[45]  C. Leclerc,et al.  Type I interferons protect neonates from acute inflammation through interleukin 10–producing B cells , 2007, The Journal of experimental medicine.

[46]  R. Garcea,et al.  MyD88 Is Required for the Formation of Long-Term Humoral Immunity to Virus Infection1 , 2007, The Journal of Immunology.

[47]  L. Audoly,et al.  Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE , 2007, Nature Immunology.

[48]  Stephen L. Nutt,et al.  Different Kinetics of Blimp-1 Induction in B Cell Subsets Revealed by Reporter Gene1 , 2007, The Journal of Immunology.

[49]  S. Akira,et al.  MyD88- and Bruton’s Tyrosine Kinase-Mediated Signals Are Essential for T Cell-Independent Pathogen-Specific IgM Responses1 , 2007, The Journal of Immunology.

[50]  G. Kelsoe,et al.  T-Independent Activation-Induced Cytidine Deaminase Expression, Class-Switch Recombination, and Antibody Production by Immature/Transitional 1 B Cells1 , 2007, The Journal of Immunology.

[51]  T. Giese,et al.  Staphylococcus aureus Protein A Triggers T Cell-Independent B Cell Proliferation by Sensitizing B Cells for TLR2 Ligands1 , 2007, The Journal of Immunology.

[52]  A. Jegerlehner,et al.  TLR9 Signaling in B Cells Determines Class Switch Recombination to IgG2a , 2007, The Journal of Immunology.

[53]  Alex K. Heer,et al.  TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses1 , 2007, The Journal of Immunology.

[54]  M. Zand,et al.  CpG DNA activation and plasma-cell differentiation of CD27- naive human B cells. , 2007, Blood.

[55]  B. Beutler,et al.  Adjuvant-Enhanced Antibody Responses in the Absence of Toll-Like Receptor Signaling , 2006, Science.

[56]  A. Marshak‐Rothstein Toll-like receptors in systemic autoimmune disease , 2006, Nature Reviews Immunology.

[57]  J. Casanova,et al.  Herpes Simplex Virus Encephalitis in Human UNC-93B Deficiency , 2006, Science.

[58]  J. W. Brewer,et al.  Evidence That Marginal Zone B Cells Possess an Enhanced Secretory Apparatus and Exhibit Superior Secretory Activity1 , 2006, The Journal of Immunology.

[59]  J. Casanova,et al.  IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease , 2006, Journal of Medical Genetics.

[60]  L. Wetzler,et al.  Toll-like receptor 2-mediated human B cell differentiation. , 2006, Clinical immunology.

[61]  L. Cardell,et al.  A distinct Toll‐like receptor repertoire in human tonsillar B cells, directly activated by Pam3CSK4, R‐837 and CpG‐2006 stimulation , 2006, Immunology.

[62]  C. Ng,et al.  BAFF costimulation of Toll‐like receptor‐activatedB‐1 cells , 2006, European journal of immunology.

[63]  R. Bataille,et al.  Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors , 2006, Leukemia.

[64]  T. Espevik,et al.  Toll-like receptors mediate proliferation and survival of multiple myeloma cells , 2006, Leukemia.

[65]  D. Nemazee,et al.  Immunology: Toll-like receptors and antibody responses , 2006, Nature.

[66]  A. Lanzavecchia,et al.  Toll‐like receptor stimulation as a third signal required for activation of human naive B cells , 2006, European journal of immunology.

[67]  N. Baumgarth,et al.  Type I IFN Receptor Signals Directly Stimulate Local B Cells Early following Influenza Virus Infection1 , 2006, The Journal of Immunology.

[68]  Bali Pulendran,et al.  Translating Innate Immunity into Immunological Memory: Implications for Vaccine Development , 2006, Cell.

[69]  S. Grinstein,et al.  The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9 , 2006, Nature Immunology.

[70]  H. S. Warren,et al.  Toll-like receptors. , 2005, Critical care medicine.

[71]  Ruslan Medzhitov,et al.  Control of B-cell responses by Toll-like receptors , 2005, Nature.

[72]  S. Akira,et al.  RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement , 2005, The Journal of experimental medicine.

[73]  B. Jungnickel,et al.  Human splenic marginal zone B cells lack expression of activation‐induced cytidine deaminase , 2005, European journal of immunology.

[74]  H. Zola,et al.  Expression of toll-like receptors on B lymphocytes. , 2005, Cellular immunology.

[75]  S. Akira,et al.  Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR21 , 2005, The Journal of Immunology.

[76]  K. Kretschmer,et al.  The Mucosal Adjuvant Macrophage-Activating Lipopeptide-2 Directly Stimulates B Lymphocytes via the TLR2 without the Need of Accessory Cells 1 , 2005, The Journal of Immunology.

[77]  T. Giese,et al.  Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN , 2005, The Journal of Immunology.

[78]  Cheng-ming Sun,et al.  Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs. , 2005, Immunity.

[79]  T. Giese,et al.  Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN1 , 2005, The Journal of Immunology.

[80]  T. Tokuhisa,et al.  CpG inhibits IgE class switch recombination through suppression of NF kappa B activity, but not through Id2 or Bcl6. , 2005, Biochemical and biophysical research communications.

[81]  G. Trinchieri,et al.  Human TLR10 Is a Functional Receptor, Expressed by B Cells and Plasmacytoid Dendritic Cells, Which Activates Gene Transcription through MyD881 , 2005, The Journal of Immunology.

[82]  J. Casanova,et al.  Inherited disorders of human Toll‐like receptor signaling: immunological implications , 2005, Immunological reviews.

[83]  D. Golenbock,et al.  Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. , 2005, The Journal of clinical investigation.

[84]  C. Snapper,et al.  Both Innate Immunity and Type 1 Humoral Immunity to Streptococcus pneumoniae Are Mediated by MyD88 but Differ in Their Relative Levels of Dependence on Toll-Like Receptor 2 , 2005, Infection and Immunity.

[85]  L. Staudt,et al.  Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. , 2004, Blood.

[86]  M. Mbow,et al.  Toll-Like Receptor 9 Can Be Expressed at the Cell Surface of Distinct Populations of Tonsils and Human Peripheral Blood Mononuclear Cells , 2004, Infection and Immunity.

[87]  B. He,et al.  CpG DNA Induces IgG Class Switch DNA Recombination by Activating Human B Cells through an Innate Pathway That Requires TLR9 and Cooperates with IL-101 , 2004, The Journal of Immunology.

[88]  S. Akira,et al.  Toll-like Receptor 9–Dependent and –Independent Dendritic Cell Activation by Chromatin–Immunoglobulin G Complexes , 2004, The Journal of experimental medicine.

[89]  J. Casanova,et al.  IRAK4 Kinase Activity Is Redundant for Interleukin-1 (IL-1) Receptor-associated Kinase Phosphorylation and IL-1 Responsiveness* , 2004, Journal of Biological Chemistry.

[90]  Ruth R. Montgomery,et al.  Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation in Borrelia burgdorferi-Infected Mice , 2004, Infection and Immunity.

[91]  L. Rönnblom,et al.  Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. , 2004, Arthritis and rheumatism.

[92]  S. Peng,et al.  CpG DNA redirects class‐switching towards "Th1‐like" Ig isotype production via TLR9 and MyD88 , 2004, European journal of immunology.

[93]  T. Giese,et al.  Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. , 2004, Blood.

[94]  J. Casanova,et al.  Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. , 2004, The Journal of pediatrics.

[95]  D. Rawlings,et al.  Signaling in transitional type 2 B cells is critical for peripheral B‐cell development , 2004, Immunological reviews.

[96]  T. Giese,et al.  IL-12p70-Dependent Th1 Induction by Human B Cells Requires Combined Activation with CD40 Ligand and CpG DNA 1 , 2004, The Journal of Immunology.

[97]  M. Shlomchik,et al.  Activation of autoreactive B cells by CpG dsDNA. , 2003, Immunity.

[98]  M. Röllinghoff,et al.  High Levels of Susceptibility and T Helper 2 Response in MyD88-Deficient Mice Infected with Leishmania major Are Interleukin-4 Dependent , 2003, Infection and Immunity.

[99]  K. Calame,et al.  Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. , 2003, Immunity.

[100]  S. Peng,et al.  T-bet regulates T-independent IgG2a class switching. , 2003, International immunology.

[101]  A. Mantovani,et al.  The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. , 2003, Blood.

[102]  Virginia Pascual,et al.  Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. , 2003, Immunity.

[103]  A. Lanzavecchia,et al.  A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. , 2003, Blood.

[104]  S. Akira,et al.  CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells , 2003, Nature Immunology.

[105]  J. Banchereau,et al.  Pyogenic Bacterial Infections in Humans with MyD88 Deficiency , 2003, Science.

[106]  M. Bachmann,et al.  Role of IgM antibodies versus B cells in influenza virus‐specific immunity , 2002, European journal of immunology.

[107]  T. Di Pucchio,et al.  Type I IFN as a Natural Adjuvant for a Protective Immune Response: Lessons from the Influenza Vaccine Model1 , 2002, The Journal of Immunology.

[108]  T. Giese,et al.  Quantitative Expression of Toll-Like Receptor 1–10 mRNA in Cellular Subsets of Human Peripheral Blood Mononuclear Cells and Sensitivity to CpG Oligodeoxynucleotides1 , 2002, The Journal of Immunology.

[109]  S. Szabo,et al.  T-bet regulates IgG class switching and pathogenic autoantibody production , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[110]  M. Shlomchik,et al.  Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors , 2002, Nature.

[111]  C. Snapper,et al.  Endogenous Pro- and Anti-Inflammatory Cytokines Differentially Regulate an In Vivo Humoral Response to Streptococcus pneumoniae , 2002, Infection and Immunity.

[112]  S. Akira,et al.  Toll-like receptors control activation of adaptive immune responses , 2001, Nature Immunology.

[113]  M. Shlomchik,et al.  Immune Complexes Present in the Sera of Autoimmune Mice Activate Rheumatoid Factor B Cells1 , 2000, The Journal of Immunology.

[114]  D. Baltimore,et al.  The p65 subunit of NF-kappa B is redundant with p50 during B cell proliferative responses, and is required for germline CH transcription and class switching to IgG3. , 1999, Journal of immunology.

[115]  J. Choe,et al.  IL‐10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells , 1998, European journal of immunology.

[116]  M. Graham,et al.  Resistance to and Recovery from Lethal Influenza Virus Infection in B Lymphocyte–deficient Mice , 1997, The Journal of experimental medicine.

[117]  C. Snapper,et al.  B cells genetically deficient in the c-Rel transactivation domain have selective defects in germline CH transcription and Ig class switching. , 1997, Journal of immunology.

[118]  Y. Obata,et al.  NF-κB RelA-deficient Lymphocytes: Normal Development of  T Cells and B Cells, Impaired Production of IgA and IgG1 and Reduced Proliferative Responses , 1997, The Journal of experimental medicine.

[119]  K. Rajewsky,et al.  Evidence for a large compartment of IgM-expressing memory B cells in humans. , 1997, Blood.

[120]  C. Snapper,et al.  B cells lacking RelB are defective in proliferative responses, but undergo normal B cell maturation to Ig secretion and Ig class switching , 1996, The Journal of experimental medicine.

[121]  D. Baltimore,et al.  B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. , 1996, Journal of immunology.

[122]  R. Zinkernagel,et al.  Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors , 1995, Journal of virology.

[123]  C. Snapper,et al.  IL-4 induction of IgE class switching by lipopolysaccharide-activated murine B cells occurs predominantly through sequential switching. , 1993, Journal of immunology.

[124]  J. Stavnezer,et al.  Induction of germ‐line immunoglobulin heavy chain transcripts by mitogens and interleukins prior to switch recombination , 1990, European journal of immunology.

[125]  F. Alt,et al.  Mitogen- and IL-4-regulated expression of germ-line Ig γ2b transcripts: Evidence for directed heavy chain class switching , 1988, Cell.

[126]  B. Glick,et al.  The chicken lacrimal gland, gland of Harder, caecal tonsil, and accessory spleens as sources of antibody-producing cells. , 1971, Cellular immunology.

[127]  A. Levinson,et al.  Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production. , 2009, The Journal of allergy and clinical immunology.

[128]  L. Audoly,et al.  Toll-like receptor 9 – dependent activation by DNA-containing immune complexes is mediated by HMGB 1 and RAGE , 2007 .

[129]  A. Aderem,et al.  TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. , 2006, The Journal of experimental medicine.

[130]  R. Ashman,et al.  TLR-9 Activation of Marginal Zone B Cells in Lupus Mice Regulates Immunity Through Increased IL-10 Production , 2005, Journal of Clinical Immunology.

[131]  S. Chen‐Kiang,et al.  Regulation of terminal differentiation of human B-cells by IL-6. , 1995, Current topics in microbiology and immunology.