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Regulation of Plasma Cell Differentiation

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B Cells in Immunity and Tolerance

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1254))

Abstract

Humoral immunity provides protection from pathogen infection, and this is mediated by antibodies that are produced by plasma cells. Plasma cells are terminally differentiated from activated B cells and are specialized for secreting antibodies. Plasma cells are generated during extrafollicular or germinal center (GC) responses, but GC-derived plasma cells are thought to be the major precursors of long-lived plasma cells, which confer long-term protection. Here, we review recent progress in our understanding of the cellular and molecular basis for plasma cell differentiation from GC B cells.

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References

  • Allen CD, Okada T, Tang HL, Cyster JG (2007) Imaging of germinal center selection events during affinity maturation. Science 315:528–531

    Article  CAS  PubMed  Google Scholar 

  • Barwick BG, Scharer CD, Bally APR, Boss JM (2016) Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation. Nat Immunol 17:1216–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barwick BG, Scharer CD, Martinez RJ, Price MJ, Wein AN, Haines RR, Bally APR, Kohlmeier JE, Boss JM (2018) B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation. Nat Commun 9:1900

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Botta D, Fuller MJ, Marquez-Lago TT, Bachus H, Bradley JE, Weinmann AS, Zajac AJ, Randall TD, Lund FE, Leon B, Ballesteros-Tato A (2017) Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol 18:1249–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calado DP, Sasaki Y, Godinho SA, Pellerin A, Kochert K, Sleckman BP, de Alboran IM, Janz M, Rodig S, Rajewsky K (2012) The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol 13:1092–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang HD, Tokoyoda K, Radbruch A (2018) Immunological memories of the bone marrow. Immunol Rev 283:86–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS, Dong C (2011) Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 17:983–988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clement RL, Daccache J, Mohammed MT, Diallo A, Blazar BR, Kuchroo VK, Lovitch SB, Sharpe AH, Sage PT (2019) Follicular regulatory T cells control humoral and allergic immunity by restraining early B cell responses. Nat Immunol 20:1360–1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Silva NS, Anderson MM, Carette A, Silva K, Heise N, Bhagat G, Klein U (2016) Transcription factors of the alternative NF-kappaB pathway are required for germinal center B-cell development. Proc Natl Acad Sci USA 113:9063–9068

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Di Niro R, Lee SJ, Vander Heiden JA, Elsner RA, Trivedi N, Bannock JM, Gupta NT, Kleinstein SH, Vigneault F, Gilbert TJ, Meffre E, McSorley SJ, Shlomchik MJ (2015) Salmonella infection drives promiscuous B cell activation followed by extrafollicular affinity maturation. Immunity 43:120–131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dominguez-Sola D, Kung J, Holmes AB, Wells VA, Mo T, Basso K, Dalla-Favera R (2015) The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity 43:1064–1074

    Article  CAS  PubMed  Google Scholar 

  • Dominguez-Sola D, Victora GD, Ying CY, Phan RT, Saito M, Nussenzweig MC, Dalla-Favera R (2012) The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol 13:1083–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fooksman DR, Schwickert TA, Victora GD, Dustin ML, Nussenzweig MC, Skokos D (2010) Development and migration of plasma cells in the mouse lymph node. Immunity 33:118–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu W, Liu X, Lin X, Feng H, Sun L, Li S, Chen H, Tang H, Lu L, Jin W, Dong C (2018) Deficiency in T follicular regulatory cells promotes autoimmunity. J Exp Med 215:815–825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ (2010) PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 11:535–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gowthaman U, Chen JS, Zhang B, Flynn WF, Lu Y, Song W, Joseph J, Gertie JA, Xu L, Collet MA, Grassmann JDS, Simoneau T, Chiang D, Berin MC, Craft JE, Weinstein JS, Williams A, Eisenbarth SC (2019) Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science 365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heise N, De Silva NS, Silva K, Carette A, Simonetti G, Pasparakis M, Klein U (2014) Germinal center B cell maintenance and differentiation are controlled by distinct NF-kappaB transcription factor subunits. J Exp Med 211:2103–2118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue T, Shinnakasu R, Ise W, Kawai C, Egawa T, Kurosaki T (2017) The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help. J Exp Med 214:1181–1198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ise W, Fujii K, Shiroguchi K, Ito A, Kometani K, Takeda K, Kawakami E, Yamashita K, Suzuki K, Okada T, Kurosaki T (2018) T follicular helper cell-germinal center B cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate. Immunity 48(702–715):e704

    Google Scholar 

  • Jacob J, Kassir R, Kelsoe G (1991) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations. J Exp Med 173:1165–1175

    Article  CAS  PubMed  Google Scholar 

  • Kometani K, Kurosaki T (2015) Differentiation and maintenance of long-lived plasma cells. Curr Opin Immunol 33:64–69

    Article  CAS  PubMed  Google Scholar 

  • Krautler NJ, Suan D, Butt D, Bourne K, Hermes JR, Chan TD, Sundling C, Kaplan W, Schofield P, Jackson J, Basten A, Christ D, Brink R (2017) Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J Exp Med 214:1259–1267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurosaki T, Kometani K, Ise W (2015) Memory B cells. Nat Rev Immunol 15:149–159

    Article  CAS  PubMed  Google Scholar 

  • Laidlaw BJ, Schmidt TH, Green JA, Allen CD, Okada T, Cyster JG (2017) The Eph-related tyrosine kinase ligand Ephrin-B1 marks germinal center and memory precursor B cells. J Exp Med 214:639–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Gadzinsky A, Gong L, Tong H, Calderon V, Li Y, Kitamura D, Klein U, Langdon WY, Hou F, Zou YR, Gu H (2018) Cbl ubiquitin ligases control B cell exit from the germinal-center reaction. Immunity 48(530–541):e536

    Google Scholar 

  • Lin KI, Angelin-Duclos C, Kuo TC, Calame K (2002) Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol 22:4771–4780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin WH, Adams WC, Nish SA, Chen YH, Yen B, Rothman NJ, Kratchmarov R, Okada T, Klein U, Reiner SL (2015) Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep 13:2203–2218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KG, Vinuesa CG (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17:975–982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu D, Xu H, Shih C, Wan Z, Ma X, Ma W, Luo D, Qi H (2015) T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature 517:214–218

    Article  CAS  PubMed  Google Scholar 

  • Lu P, Shih C, Qi H (2017) Ephrin B1-mediated repulsion and signaling control germinal center T cell territoriality and function. Science 356

    Article  PubMed  CAS  Google Scholar 

  • Luo W, Weisel F, Shlomchik MJ (2018) B cell receptor and CD40 signaling are rewired for synergistic induction of the c-Myc transcription factor in germinal center B cells. Immunity 48(313–326):e315

    Google Scholar 

  • Maceiras AR, Almeida SCP, Mariotti-Ferrandiz E, Chaara W, Jebbawi F, Six A, Hori S, Klatzmann D, Faro J, Graca L (2017) T follicular helper and T follicular regulatory cells have different TCR specificity. Nat Commun 8:15067

    Article  PubMed  PubMed Central  Google Scholar 

  • MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM, Zuniga E, Cook MC, Vinuesa CG (2003) Extrafollicular antibody responses. Immunol Rev 194:8–18

    Article  CAS  PubMed  Google Scholar 

  • McHeyzer-Williams MG, McLean MJ, Lalor PA, Nossal GJ (1993) Antigen-driven B cell differentiation in vivo. J Exp Med 178:295–307

    Article  CAS  PubMed  Google Scholar 

  • Meyer-Hermann M, Mohr E, Pelletier N, Zhang Y, Victora GD, Toellner KM (2012) A theory of germinal center B cell selection, division, and exit. Cell Rep 2:162–174

    Article  CAS  PubMed  Google Scholar 

  • Minnich M, Tagoh H, Bonelt P, Axelsson E, Fischer M, Cebolla B, Tarakhovsky A, Nutt SL, Jaritz M, Busslinger M (2016) Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation. Nat Immunol 17:331–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM (2015) The generation of antibody-secreting plasma cells. Nat Rev Immunol 15:160–171

    Article  CAS  PubMed  Google Scholar 

  • Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD (2011) The genetic network controlling plasma cell differentiation. Semin Immunol 23:341–349

    Article  CAS  PubMed  Google Scholar 

  • Ochiai K, Maienschein-Cline M, Simonetti G, Chen J, Rosenthal R, Brink R, Chong AS, Klein U, Dinner AR, Singh H, Sciammas R (2013) Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 38:918–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R (2006) Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med 203:1081–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phan TG, Paus D, Chan TD, Turner ML, Nutt SL, Basten A, Brink R (2006) High affinity germinal center B cells are actively selected into the plasma cell compartment. J Exp Med 203:2419–2424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sage PT, Sharpe AH (2016) T follicular regulatory cells. Immunol Rev 271:246–259

    Article  CAS  PubMed  Google Scholar 

  • Sander S, Chu VT, Yasuda T, Franklin A, Graf R, Calado DP, Li S, Imami K, Selbach M, Di Virgilio M, Bullinger L, Rajewsky K (2015) PI3 kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity 43:1075–1086

    Article  CAS  PubMed  Google Scholar 

  • Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H (2006) Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25:225–236

    Article  CAS  PubMed  Google Scholar 

  • Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A, Giltnane JM, Yang L, Zhao H, Calame K, Staudt LM (2002) Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17:51–62

    Article  CAS  PubMed  Google Scholar 

  • Shi J, Hou S, Fang Q, Liu X, Liu X, Qi H (2018) PD-1 controls follicular T helper cell positioning and function. Immunity 49(264–274):e264

    Article  CAS  Google Scholar 

  • 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 16:663–673

    Article  CAS  PubMed  Google Scholar 

  • Shinnakasu R, Inoue T, Kometani K, Moriyama S, Adachi Y, Nakayama M, Takahashi Y, Fukuyama H, Okada T, Kurosaki T (2016) Regulated selection of germinal-center cells into the memory B cell compartment. Nat Immunol 17:861–869

    Article  CAS  PubMed  Google Scholar 

  • Smith KG, Light A, Nossal GJ, Tarlinton DM (1997) The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J 16:2996–3006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suan D, Krautler NJ, Maag JLV, Butt D, Bourne K, Hermes JR, Avery DT, Young C, Statham A, Elliott M, Dinger ME, Basten A, Tangye SG, Brink R (2017) CCR6 defines memory B cell precursors in mouse and human germinal centers, revealing light-zone location and predominant low antigen affinity. Immunity 47(1142–1153):e1144

    Google Scholar 

  • Tellier J, Shi W, Minnich M, Liao Y, Crawford S, Smyth GK, Kallies A, Busslinger M, Nutt SL (2016) Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response. Nat Immunol 17:323–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomayko MM, Steinel NC, Anderson SM, Shlomchik MJ (2010) Cutting edge: hierarchy of maturity of murine memory B cell subsets. J Immunol 185:7146–7150

    Article  CAS  PubMed  Google Scholar 

  • Victora GD, Nussenzweig MC (2012) Germinal centers. Annu Rev Immunol 30:429–457

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Shi J, Yan J, Xiao Z, Hou X, Lu P, Hou S, Mao T, Liu W, Ma Y, Zhang L, Yang X, Qi H (2017) Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat Immunol 18:921–930

    Article  CAS  PubMed  Google Scholar 

  • Weinstein JS, Herman EI, Lainez B, Licona-Limon P, Esplugues E, Flavell R, Craft J (2016) TFH cells progressively differentiate to regulate the germinal center response. Nat Immunol 17:1197–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weisel FJ, Zuccarino-Catania GV, Chikina M, Shlomchik MJ (2016) A temporal switch in the germinal center determines differential output of memory B and plasma cells. Immunity 44:116–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • William J, Euler C, Christensen S, Shlomchik MJ (2002) Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297:2066–2070

    Article  CAS  PubMed  Google Scholar 

  • Wing JB, Kitagawa Y, Locci M, Hume H, Tay C, Morita T, Kidani Y, Matsuda K, Inoue T, Kurosaki T, Crotty S, Coban C, Ohkura N, Sakaguchi S (2017) A distinct subpopulation of CD25(-) T-follicular regulatory cells localizes in the germinal centers. Proc Natl Acad Sci USA 114:E6400–E6409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wollenberg I, Agua-Doce A, Hernandez A, Almeida C, Oliveira VG, Faro J, Graca L (2011) Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J Immunol 187:4553–4560

    Article  CAS  PubMed  Google Scholar 

  • Yan H, Wu L, Shih C, Hou S, Shi J, Mao T, Chen W, Melvin B, Rigby RJ, Chen Y, Jiang H, Friedel RH, Vinuesa CG, Qi H (2017) Plexin B2 and Semaphorin 4C guide T cell recruitment and function in the germinal center. Cell Rep 19:995–1007

    Article  CAS  PubMed  Google Scholar 

  • Zaretsky I, Atrakchi O, Mazor RD, Stoler-Barak L, Biram A, Feigelson SW, Gitlin AD, Engelhardt B, Shulman Z (2017) ICAMs support B cell interactions with T follicular helper cells and promote clonal selection. J Exp Med 214:3435–3448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan

    W. Ise & T. Kurosaki

  2. Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, 230-0045, Japan

    T. Kurosaki

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  1. W. Ise
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Correspondence to W. Ise .

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Editors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Ji-Yang Wang

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Ise, W., Kurosaki, T. (2020). Regulation of Plasma Cell Differentiation. In: Wang, JY. (eds) B Cells in Immunity and Tolerance. Advances in Experimental Medicine and Biology, vol 1254. Springer, Singapore. https://doi.org/10.1007/978-981-15-3532-1_6

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