• 1
    Medzhitov, R., Approaching the asymptote: 20 years later. Immunity 2009. 30: 766775.
  • 2
    Cooper, M. D.andAlder, M. N., The evolution of adaptive immune systems. Cell 2006. 124: 815822.
  • 3
    Balazs, M., Martin, F., Zhou, T. and Kearney, J., Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity 2002. 17: 341352.
  • 4
    King, I. L., Fortier, A., Tighe, M., Dibble, J., Watts, G. F., Veerapen, N., Haberman, A. al.,Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nat. Immunol. 2012. 13: 4450.
  • 5
    Chang, P. P., Barral, P., Fitch, J., Pratama, A., Ma, C. S., Kallies, A., Hogan, J. J. et al., Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat. Immunol. 2012. 13: 3543.
  • 6
    Bassing, C. H., Swat, W. and Alt, F. W., The mechanism and regulation of chromosomal V(D)J recombination. Cell 2002. 109 Suppl: S45S55.
  • 7
    MacLennan, I. C., Germinal centers. Annu. Rev. Immunol. 1994. 12: 117139.
  • 8
    Schaerli, P., Willimann, K., Lang, A. B., Lipp, M., Loetscher, P. and Moser, B., CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 2000. 192: 15531562.
  • 9
    Breitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M. and Forster, R., Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 2000. 192: 15451552.
  • 10
    Johnston, R. J., Poholek, A. C., DiToro, D., Yusuf, I., Eto, D., Barnett, B., Dent, A. L. et al., Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009. 325: 10061010.
  • 11
    Bauquet, A. T., Jin, H., Paterson, A. M., Mitsdoerffer, M., Ho, I. C., Sharpe, A. H. and Kuchroo, V. K., The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 2009. 10: 167175.
  • 12
    Yu, D., Rao, S., Tsai, L. M., Lee, S. K., He, Y., Sutcliffe, E. L., Srivastava, M. et al., The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009. 31: 457468.
  • 13
    Kitano, M., Moriyama, S., Ando, Y., Hikida, M., Mori, Y., Kurosaki, T. and Okada, T., Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 2011. 34: 961972.
  • 14
    Lee, S. K., Rigby, R. J., Zotos, D., Tsai, L. M., Kawamoto, S., Marshall, J. L., Ramiscal, R. R. et al., B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J. Exp. Med. 2011. 208: 13771388.
  • 15
    Choi, Y. S., Kageyama, R., Eto, D., Escobar, T. C., Johnston, R. J., Monticelli, L., Lao, C. et al., ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 2011. 34: 932946.
  • 16
    Zaretsky, A. G., Taylor, J. J., King, I. L., Marshall, F. A., Mohrs, M. and Pearce, E. J., T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 2009. 206: 991999.
  • 17
    King, I. L. and Mohrs, M., IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 2009. 206: 10011007.
  • 18
    Linterman, M. A., Beaton, L., Yu, D., Ramiscal, R. R., Srivastava, M., Hogan, J. J., Verma, N. K. et al., IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 2010. 207: 353363.
  • 19
    Luthje, K., Kallies, A., Shimohakamada, Y., Belz, G. T., Light, A., Tarlinton, D. M. and Nutt, S. L., The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat. Immunol. 2012. 13: 491498.
  • 20
    Linterman, M. A., Pierson, W., Lee, S. K., Kallies, A., Kawamoto, S., Rayner, T. F., Srivastava, M. et al., Foxp3 +follicular regulatory T cells control the germinal center response. Nat. Med. 2011. 17: 975982.
  • 21
    Chung, Y., Tanaka, S., Chu, F., Nurieva, R. I., Martinez, G. J., Rawal, S., Wang, Y. H. et al., Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 2011. 17: 983988.
  • 22
    Leonardo, S. M., De Santis, J. L., Malherbe, L. P. and Gauld, S. B., Cutting edge: in the absence of regulatory T cells, a unique th cell population expands and leads to a loss of B cell anergy. J. Immunol. 2012. 188: 52235226.
  • 23
    Guinamard, R., Okigaki, M., Schlessinger, J. and Ravetch, J. V., Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat. Immunol. 2000. 1: 3136.
  • 24
    Martin, F., Oliver, A. M. and Kearney, J. F., Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 2001. 14: 617629.
  • 25
    Kruetzmann, S., Rosado, M. M., Weber, H., Germing, U., Tournilhac, O., Peter, H. H., Berner, R. et al., Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J. Exp. Med. 2003. 197: 939945.
  • 26
    Alugupalli, K. R., Leong, J. M., Woodland, R. T., Muramatsu, M., Honjo, T. and Gerstein, R. M., B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity 2004. 21: 379390.
  • 27
    Weller, S., Braun, M. C., Tan, B. K., Rosenwald, A., Cordier, C., Conley, M. E., Plebani, A. et al., Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 2004. 104: 36473654.
  • 28
    Cariappa, A., Mazo, I. B., Chase, C., Shi, H. N., Liu, H., Li, Q., Rose, H. et al., Perisinusoidal B cells in the bone marrow participate in T-independent responses to blood-borne microbes. Immunity 2005. 23: 397407.
  • 29
    Choi, Y. S. and Baumgarth, N., Dual role for B-1a cells in immunity to influenza virus infection. J. Exp. Med. 2008. 205: 30533064.
  • 30
    Puga, I., Cols, M., Barra, C. M., He, B., Cassis, L., Gentile, M., Comerma, L. et al., B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 2012. 13: 170180.
  • 31
    Macpherson, A. J., Gatto, D., Sainsbury, E., Harriman, G. R., Hengartner, H. and Zinkernagel, R. M., A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000. 288: 22222226.
  • 32
    Colino, J., Shen, Y. and Snapper, C. M., Dendritic cells pulsed with intact Streptococcus pneumoniae elicit both protein- and polysaccharide-specific immunoglobulin isotype responses in vivo through distinct mechanisms. J. Exp. Med. 2002. 195: 113.
  • 33
    Karlsson, M. C., Guinamard, R., Bolland, S., Sankala, M., Steinman, R. M. and Ravetch, J. V., Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J. Exp. Med. 2003. 198: 333340.
  • 34
    Macpherson, A. J. and Uhr, T., Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004. 303: 16621665.
  • 35
    von Bulow, G. U., van Deursen, J. M. and Bram, R. J., Regulation of the T-independent humoral response by TACI. Immunity 2001. 14: 573582.
  • 36
    Litinskiy, M. B., Nardelli, B., Hilbert, D. M., He, B., Schaffer, A., Casali, P. and Cerutti, A., DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 2002. 3: 822829.
  • 37
    Scapini, P., Nardelli, B., Nadali, G., Calzetti, F., Pizzolo, G., Montecucco, C. and Cassatella, M. A., G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J .Exp. Med. 2003. 197: 297302.
  • 38
    He, B., Xu, W., Santini, P. A., Polydorides, A. D., Chiu, A., Estrella, J., Shan, M. et al., Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 2007. 26: 812826.
  • 39
    He, B., Santamaria, R., Xu, W., Cols, M., Chen, K., Puga, I., Shan, M. et al., The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat. Immunol. 2010. 11: 836845.
  • 40
    Song, H. and Cerny, J., 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. 2003. 198: 19231935.
  • 41
    Cinamon, G., Zachariah, M. A., Lam, O. M., Foss, F. W., Jr. and Cyster, J. G., Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat. Immunol. 2008. 9: 5462.
  • 42
    Tsuji, M., Suzuki, K., Kitamura, H., Maruya, M., Kinoshita, K., Ivanov, II, Itoh, K. et al., Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 2008. 29: 261271.
  • 43
    Kerfoot, S. M., Yaari, G., Patel, J. R., Johnson, K. L., Gonzalez, D. G., Kleinstein, S. H. and Haberman, A. M., Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 2011. 34: 947960.
  • 44
    Baumjohann, D., Okada, T. and Ansel, K. M., Cutting edge: distinct waves of BCL6 expression during T follicular helper cell development. J. Immunol. 2011. 187: 20892092.
  • 45
    Chan, T. D., Gatto, D., Wood, K., Camidge, T., Basten, A. and Brink, R., Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J. Immunol. 2009. 183: 31393149.
  • 46
    Toellner, K. M., Gulbranson-Judge, A., Taylor, D. R., Sze, D. M. and MacLennan, I. C., Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation. J. Exp. Med. 1996. 183: 23032312.
  • 47
    Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T., Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000. 102: 553563.
  • 48
    Pape, K. A., Kouskoff, V., Nemazee, D., Tang, H. L., Cyster, J. G., Tze, L. E., Hippen, K. L. et al., Visualization of the genesis and fate of isotype-switched B cells during a primary immune response. J. Exp. Med. 2003. 197: 16771687.
  • 49
    Kolar, G. R., Mehta, D., Pelayo, R. and Capra, J. D., A novel human B cell subpopulation representing the initial germinal center population to express AID. Blood 2007. 109: 25452552.
  • 50
    Papavasiliou, F. N. and Schatz, D. G., Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 2002. 109 Suppl.: S35S44.
  • 51
    Chaudhuri, J. and Alt, F. W., Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat. Rev. Immunol. 2004. 4: 541552.
  • 52
    Chen, K., Xu, W., Wilson, M., He, B., Miller, N. W., Bengten, E., Edholm, E. S. et al., Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat. Immunol. 2009. 10: 889898.
  • 53
    Liu, Y. J., Barthelemy, C., de Bouteiller, O., Arpin, C., Durand, I. and Banchereau, J., Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by rapid up-regulation of B7–1 and B7–2. Immunity 1995. 2: 239248.
  • 54
    Liu, Y. J., Malisan, F., de Bouteiller, O., Guret, C., Lebecque, S., Banchereau, J., Mills, F. C. et al., Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 1996. 4: 241250.
  • 55
    Crouch, E. E., Li, Z., Takizawa, M., Fichtner-Feigl, S., Gourzi, P., Montano, C., Feigenbaum, L. et al., Regulation of AID expression in the immune response. J. Exp. Med. 2007. 204: 11451156.
  • 56
    Allen, C. D., Okada, T., Tang, H. L. and Cyster, J. G., Imaging of germinal center selection events during affinity maturation. Science 2007. 315: 528531.
  • 57
    Schwickert, T. A., Lindquist, R. L., Shakhar, G., Livshits, G., Skokos, D., Kosco-Vilbois, M. H., Dustin, M. L. et al., In vivo imaging of germinal centres reveals a dynamic open structure. Nature 2007. 446: 8387.
  • 58
    Schmitt, N., Morita, R., Bourdery, L., Bentebibel, S. E., Zurawski, S. M., Banchereau, J. and Ueno, H., Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 2009. 31: 158169.
  • 59
    Ansel, K. M., McHeyzer-Williams, L. J., Ngo, V. N., McHeyzer-Williams, M. G. and Cyster, J. G., In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 1999. 190: 11231134.
  • 60
    Vinuesa, C. G., Tangye, S. G., Moser, B. and Mackay, C. R., Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 2005. 5: 853865.
  • 61
    Gunn, M. D., Ngo, V. N., Ansel, K. M., Ekland, E. H., Cyster, J. G. and Williams, L. T., A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 1998. 391: 799803.
  • 62
    Ozaki, K., Spolski, R., Feng, C. G., Qi, C. F., Cheng, J., Sher, A., Morse, H. C., 3rd et al., A critical role for IL-21 in regulating immunoglobulin production. Science 2002. 298: 16301634.
  • 63
    Lohning, M., Hutloff, A., Kallinich, T., Mages, H. W., Bonhagen, K., Radbruch, A., Hamelmann, E. et al., Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J. Exp. Med. 2003. 197: 181193.
  • 64
    Pelletier, N., McHeyzer-Williams, L. J., Wong, K. A., Urich, E., Fazilleau, N. and McHeyzer-Williams, M. G., Plasma cells negatively regulate the follicular helper T cell program. Nat. Immunol. 2010. 11: 11101118.
  • 65
    Dogan, I., Bertocci, B., Vilmont, V., Delbos, F., Megret, J., Storck, S., Reynaud, C. A. et al., Multiple layers of B cell memory with different effector functions. Nat. Immunol. 2009. 10: 12921299.
  • 66
    Blink, E. J., Light, A., Kallies, A., Nutt, S. L., Hodgkin, P. D. and Tarlinton, D. M., Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J. Exp. Med. 2005. 201: 545554.
  • 67
    Bernasconi, N. L., Traggiai, E. and Lanzavecchia, A., Maintenance of serological memory by polyclonal activation of human memory B cells. Science 2002. 298: 21992202.
  • 68
    Shapiro-Shelef, M., Lin, K. I., McHeyzer-Williams, L. J., Liao, J., McHeyzer-Williams, M. G. and Calame, K., Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 2003. 19: 607620.
  • 69
    Phan, T. G., Paus, D., Chan, T. D., Turner, M. L., Nutt, S. L., Basten, A. and Brink, R., High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 2006. 203: 24192424.
  • 70
    Chu, V. T., Frohlich, A., Steinhauser, G., Scheel, T., Roch, T., Fillatreau, S., Lee, J. J. et al., Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat. Immunol. 2011. 12: 151159.
  • 71
    Silk, J. D., Hermans, I. F., Gileadi, U., Chong, T. W., Shepherd, D., Salio, M., Mathew, B. et al., Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. J. Clin. Invest. 2004. 114: 18001811.
  • 72
    Barral, P., Polzella, P., Bruckbauer, A., van Rooijen, N., Besra, G. S., Cerundolo, V. and Batista, F. D., CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nat. Immunol. 2010. 11: 303312.
  • 73
    Galli, G., Pittoni, P., Tonti, E., Malzone, C., Uematsu, Y., Tortoli, M., Maione, D. et al., Invariant NKT cells sustain specific B cell responses and memory. Proc. Natl. Acad. Sci. USA 2007. 104: 39843989.
  • 74
    Barral, P., Eckl-Dorna, J., Harwood, N. E., De Santo, C., Salio, M., Illarionov, P., Besra, G. S. et al., B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc. Natl. Acad. Sci. USA 2008. 105: 83458350.
  • 75
    Casola, S., Otipoby, K. L., Alimzhanov, M., Humme, S., Uyttersprot, N., Kutok, J. L., Carroll, M. C. et al., B cell receptor signal strength determines B cell fate. Nat. Immunol. 2004. 5: 317327.
  • 76
    Suzuki, K., Maruya, M., Kawamoto, S., Sitnik, K., Kitamura, H., Agace, W. W. and Fagarasan, S., The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut. Immunity 2010. 33: 7183.
  • 77
    Dullaers, M., Li, D., Xue, Y., Ni, L., Gayet, I., Morita, R., Ueno, H. et al., A T cell-dependent mechanism for the induction of human mucosal homing immunoglobulin A-secreting plasmablasts. Immunity 2009. 30: 120129.
  • 78
    Bergqvist, P., Stensson, A., Lycke, N. Y. and Bemark, M., T cell-independent IgA class switch recombination is restricted to the GALT and occurs prior to manifest germinal center formation. J. Immunol. 2010. 184: 35453553.
  • 79
    Tezuka, H., Abe, Y., Iwata, M., Takeuchi, H., Ishikawa, H., Matsushita, M., Shiohara, T. et al., Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 2007. 448: 929933.
  • 80
    Fritz, J. H., Rojas, O. L., Simard, N., McCarthy, D. D., Hapfelmeier, S., Rubino, S., Robertson, S. J. et al., Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 2012. 481: 199203.
  • 81
    Tezuka, H., Abe, Y., Asano, J., Sato, T., Liu, J., Iwata, M. and Ohteki, T., Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity 2011. 34: 247257.
  • 82
    Fagarasan, S., Kawamoto, S., Kanagawa, O. and Suzuki, K., Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 2010. 28: 243273.
  • 83
    Cerutti, A., Chen, K. and Chorny, A., Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 2011. 29: 273293.
  • 84
    Uematsu S., Fujimoto, K., Ho Jang, M., Yang, B.-G., Jung, Y.-J., Nishiyama, M., Sato, S., et al., Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol 2008. 9: 769776.
  • 85
    Xu, W., He, B., Chiu, A., Chadburn, A., Shan, M., Buldys, M., Ding, A. et al., Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat. Immunol. 2007. 8: 294303.
  • 86
    Niess, J. H., Brand, S., Gu, X., Landsman, L., Jung, S., McCormick, B. A., Vyas, J. M. et al., CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 2005. 307: 254258.
  • 87
    Chieppa, M., Rescigno, M., Huang, A. Y. and Germain, R. N., Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 2006. 203: 28412852.
  • 88
    Lelouard, H., Fallet, M., de Bovis, B., Meresse, S. and Gorvel, J. P., Peyer's patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. Gastroenterology 2012. 142: 592601 e593.
  • 89
    McDole, J. R., Wheeler, L. W., McDonald, K. G., Wang, B., Konjufca, V., Knoop, K. A., Newberry, R. D. et al., Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 2012. 483: 345349.
  • 90
    Bergtold, A., Desai, D. D., Gavhane, A. and Clynes, R., Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 2005. 23: 503514.
  • 91
    O'Connor, B. P., Raman, V. S., Erickson, L. D., Cook, W. J., Weaver, L. K., Ahonen, C., Lin, L. L. et al., BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 2004. 199: 9198.
  • 92
    Martin, F. and Kearney, J. F., Marginal-zone B cells. Nat. Rev. Immunol. 2002. 2: 323335.
  • 93
    Weill, J. C., Weller, S. and Reynaud, C. A., Human marginal zone B cells. Annu. Rev. Immunol. 2009. 27: 267285.
  • 94
    Huard, B., McKee, T., Bosshard, C., Durual, S., Matthes, T., Myit, S., Donze, O. et al., APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa. J. Clin. Invest. 2008. 118: 28872895.
  • 95
    Mantovani, A., Cassatella, M. A., Costantini, C. and Jaillon, S., Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 2011. 11: 519531.
  • 96
    Weller, S., Faili, A., Garcia, C., Braun, M. C., Le Deist, F. F., de Saint Basile, G. G., Hermine, O. et al., CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. Proc. Natl. Acad. Sci. USA 2001. 98: 11661170.
  • 97
    Scheeren, F. A., Nagasawa, M., Weijer, K., Cupedo, T., Kirberg, J., Legrand, N. and Spits, H., T cell-independent development and induction of somatic hypermutation in human IgM+ IgD+ CD27+ B cells. J. Exp. Med. 2008. 205: 20332042.
  • 98
    Aranburu, A., Ceccarelli, S., Giorda, E., Lasorella, R., Ballatore, G. and Carsetti, R., TLR ligation triggers somatic hypermutation in transitional B cells inducing the generation of IgM memory B cells. J. Immunol. 2010. 185: 72937301.
  • 99
    Berkowska, M. A., Driessen, G. J., Bikos, V., Grosserichter-Wagener, C., Stamatopoulos, K., Cerutti, A., He, B. et al., Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways. Blood 2011. 118: 21502158.
  • 100
    Herlands, R. A., Christensen, S. R., Sweet, R. A., Hershberg, U. and Shlomchik, M. J., T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity 2008. 29: 249260.
  • 101
    Seifert, M. and Kuppers, R., Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation. J. Exp. Med. 2009. 206: 26592669.
  • 102
    Toellner, K. M., Jenkinson, W. E., Taylor, D. R., Khan, M., Sze, D. M., Sansom, D. M., Vinuesa, C. G. et al., Low-level hypermutation in T cell-independent germinal centers compared with high mutation rates associated with T cell-dependent germinal centers. J. Exp. Med. 2002. 195: 383389.
  • 103
    Mao, C., Jiang, L., Melo-Jorge, M., Puthenveetil, M., Zhang, X., Carroll, M. C. and Imanishi-Kari, T., T cell-independent somatic hypermutation in murine B cells with an immature phenotype. Immunity 2004. 20: 133144.
  • 104
    Lande, R., Ganguly, D., Facchinetti, V., Frasca, L., Conrad, C., Gregorio, J., Meller, S. et al., Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 2011. 3: 73ra19.
  • 105
    Garcia-Romo, G. S., Caielli, S., Vega, B., Connolly, J., Allantaz, F., Xu, Z., Punaro, M. et al., Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 2011. 3: 73ra20.
  • 106
    He, B., Qiao, X. and Cerutti, A., CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J. Immunol. 2004. 173: 44794491.
  • 107
    Capolunghi, F., Cascioli, S., Giorda, E., Rosado, M. M., Plebani, A., Auriti, C., Seganti, G. et al., CpG drives human transitional B cells to terminal differentiation and production of natural antibodies. J. Immunol. 2008. 180: 800808.
  • 108
    Manz, R. A., Hauser, A. E., Hiepe, F. and Radbruch, A., Maintenance of serum antibody levels. Annu. Rev. Immunol. 2005. 23: 367386.
  • 109
    Winter, O., Moser, K., Mohr, E., Zotos, D., Kaminski, H., Szyska, M., Roth, K. et al., Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 2010. 116: 18671875.
  • 110
    Galli, S. J., Grimbaldeston, M. and Tsai, M., Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat. Rev. Immunol. 2008. 8: 478486.
  • 111
    Galli, S. J. and Hammel, I., Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science 1984. 226: 710713.
  • 112
    Gauchat, J. F., Henchoz, S., Mazzei, G., Aubry, J. P., Brunner, T., Blasey, H., Life, P. et al., Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 1993. 365: 340343.
  • 113
    Pawankar, R., Okuda, M., Yssel, H., Okumura, K. and Ra, C., Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the Fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J. Clin. Invest. 1997. 99: 14921499.
  • 114
    Jutel, M., Watanabe, T., Klunker, S., Akdis, M., Thomet, O. A., Malolepszy, J., Zak-Nejmark, T. et al., Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 2001. 413: 420425.
  • 115
    Ott, V. L., Cambier, J. C., Kappler, J., Marrack, P. and Swanson, B. J., Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat. Immunol. 2003. 4: 974981.
  • 116
    McLachlan, J. B., Hart, J. P., Pizzo, S. V., Shelburne, C. P., Staats, H. F., Gunn, M. D. and Abraham, S. N., Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nat. Immunol. 2003. 4: 11991205.
  • 117
    Gri, G., Piconese, S., Frossi, B., Manfroi, V., Merluzzi, S., Tripodo, C., Viola, A. et al., CD4+CD25 +regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 2008. 29: 771781.
  • 118
    Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. and Elson, C. O., A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl. Acad. Sci. USA 2009. 106: 1925619261.
  • 119
    Tsuji, M., Komatsu, N., Kawamoto, S., Suzuki, K., Kanagawa, O., Honjo, T., Hori, S. et al., Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 2009. 323: 14881492.
  • 120
    Geuking, M. B., Cahenzli, J., Lawson, M. A., Ng, D. C., Slack, E., Hapfelmeier, S., McCoy, K. D. et al., Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 2011. 34: 794806.
  • 121
    Merluzzi, S., Frossi, B., Gri, G., Parusso, S., Tripodo, C. and Pucillo, C., Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells. Blood 2010. 115: 28102817.
  • 122
    Sokol, C. L., Barton, G. M., Farr, A. G. and Medzhitov, R., A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat. Immunol. 2008. 9: 310318.
  • 123
    Yoshimoto, T., Yasuda, K., Tanaka, H., Nakahira, M., Imai, Y., Fujimori, Y. and Nakanishi, K., Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4(+) T cells. Nat. Immunol. 2009. 10: 706712.
  • 124
    Sokol, C. L., Chu, N. Q., Yu, S., Nish, S. A., Laufer, T. M. and Medzhitov, R., Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol. 2009. 10: 713720.
  • 125
    Perrigoue, J. G., Saenz, S. A., Siracusa, M. C., Allenspach, E. J., Taylor, B. C., Giacomin, P. R., Nair, M. G. et al., MHC class II-dependent basophil-CD4(+) T cell interactions promote T(H)2 cytokine-dependent immunity. Nat. Immunol. 2009. 10: 697705.
  • 126
    Denzel, A., Maus, U. A., Rodriguez Gomez, M., Moll, C., Niedermeier, M., Winter, C., Maus, R. et al., Basophils enhance immunological memory responses. Nat. Immunol. 2008. 9: 733742.
  • 127
    Hammad, H., Plantinga, M., Deswarte, K., Pouliot, P., Willart, M. A., Kool, M., Muskens, F. et al., Inflammatory dendritic cells–not basophils–are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J. Exp. Med. 2010. 207: 20972111.
  • 128
    Arpin, C., de Bouteiller, O., Razanajaona, D., Fugier-Vivier, I., Briere, F., Banchereau, J., Lebecque, S. et al., The normal counterpart of IgD myeloma cells in germinal center displays extensively mutated IgVH gene, Cmu-Cdelta switch, and lambda light chain expression. J. Exp. Med. 1998. 187: 11691178.
  • 129
    Liu, Y. J., de Bouteiller, O., Arpin, C., Briere, F., Galibert, L., Ho, S., Martinez-Valdez, H. et al., Normal human IgD+IgM- germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts. Immunity 1996. 4: 603613.
  • 130
    Koelsch, K., Zheng, N. Y., Zhang, Q., Duty, A., Helms, C., Mathias, M. D., Jared, M. et al., Mature B cells class switched to IgD are autoreactive in healthy individuals. J. Clin. Invest. 2007. 117: 15581565.