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Normal B and T lymphocyte development

Jon C Aster, MD
Francisco A Bonilla, MD, PhD
Section Editors
Arnold S Freedman, MD
E Richard Stiehm, MD
Deputy Editor
Alan G Rosmarin, MD


Lymphocyte development involves a complex series of tightly choreographed events. Current models are based on studies of genetically engineered mice, in vitro culture systems that support lymphoid development, and rare patients with genetic forms of immunodeficiency. The process is orchestrated by many different genes, which often act at specific stages of B or T cell differentiation. These genes variously encode several different types of factors, including lineage-specific transcription factors, growth factors, and chemokines; DNA recombinases (RAG1 and RAG2) and terminal deoxytransferase (TdT), which direct the rearrangement and diversification of B and T cell antigen receptor genes, respectively; and the DNA modifying enzyme activation-induced cytosine deaminase (AID), which is needed for immunoglobulin class-switching and somatic hypermutation, a phenomenon that is required for the production of high affinity antibodies.

Of clinical importance, many lymphoid malignancies appear to be the neoplastic counterparts of cells "arrested" at particular stages of lymphoid differentiation, as judged by cytologic appearance, patterns of growth, immunophenotype, and genetic features. This insight serves as the organizing theme for the current World Health Organization (WHO) Classification of Lymphoid Malignancies [1], which sorts lymphoid tumors according to their apparent cell of origin.

This topic review will focus on the early events of B and T cell development and provide a description of some of the markers that define both early and later stages of B and T cells. Development of the immune system in fetal and neonatal life is discussed separately. (See "The development of immune cells in the fetus and neonate".)


Lymphoid tissues are subdivided into primary and secondary lymphoid organs. The primary lymphoid tissues responsible for the initial generation of B and T lymphocytes are the bone marrow and thymus, respectively.

Secondary lymphoid tissues include lymph nodes, spleen, tonsils, and the aggregations of lymphoid tissue located in the gastrointestinal and respiratory tracts. Within these lymphoid organs, B and T lymphocytes tend to home to different domains, leading to the segregation of B and T cells. Specifically, B cells mainly localize to follicles, whereas T cells mainly localize to interfollicular areas. Non-lymphoid cells (eg, dendritic cells, monocytes/macrophages, endothelial cells, and follicular dendritic cells) contribute to the formation of these distinct microenvironments, within which specific cell-cell interactions occur that are required for the generation of cellular and humoral immune responses. (See "The adaptive cellular immune response" and "The humoral immune response".)


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  1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Cancer, Lyon 2008.
  2. Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 2008; 132:631.
  3. Yona S, Kim KW, Wolf Y, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 2013; 38:79.
  4. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330:841.
  5. Bertrand JY, Chi NC, Santoso B, et al. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 2010; 464:108.
  6. Kissa K, Herbomel P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 2010; 464:112.
  7. Ditadi A, Sturgeon CM, Tober J, et al. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat Cell Biol 2015; 17:580.
  8. Rothenberg EV. Transcriptional control of early T and B cell developmental choices. Annu Rev Immunol 2014; 32:283.
  9. Dykstra B, Kent D, Bowie M, et al. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 2007; 1:218.
  10. Benz C, Copley MR, Kent DG, et al. Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 2012; 10:273.
  11. Nuñez C, Nishimoto N, Gartland GL, et al. B cells are generated throughout life in humans. J Immunol 1996; 156:866.
  12. LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008; 112:1570.
  13. Björck P, Kincade PW. CD19+ pro-B cells can give rise to dendritic cells in vitro. J Immunol 1998; 161:5795.
  14. Dorshkind K, Montecino-Rodriguez E. Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential. Nat Rev Immunol 2007; 7:213.
  15. Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science 2002; 296:1641.
  16. Tedder TF, Zhou LJ, Engel P. The CD19/CD21 signal transduction complex of B lymphocytes. Immunol Today 1994; 15:437.
  17. He XY, Antao VP, Basila D, et al. Isolation and molecular characterization of the human CD34 gene. Blood 1992; 79:2296.
  18. Melchers F, Karasuyama H, Haasner D, et al. The surrogate light chain in B-cell development. Immunol Today 1993; 14:60.
  19. Schuh W, Meister S, Roth E, Jäck HM. Cutting edge: signaling and cell surface expression of a mu H chain in the absence of lambda 5: a paradigm revisited. J Immunol 2003; 171:3343.
  20. Yel L, Minegishi Y, Coustan-Smith E, et al. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N Engl J Med 1996; 335:1486.
  21. Minegishi Y, Coustan-Smith E, Wang YH, et al. Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia. J Exp Med 1998; 187:71.
  22. Minegishi Y, Coustan-Smith E, Rapalus L, et al. Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J Clin Invest 1999; 104:1115.
  23. Ferrari S, Lougaris V, Caraffi S, et al. Mutations of the Igbeta gene cause agammaglobulinemia in man. J Exp Med 2007; 204:2047.
  24. Vetrie D, Vorechovský I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361:226.
  25. Minegishi Y, Rohrer J, Coustan-Smith E, et al. An essential role for BLNK in human B cell development. Science 1999; 286:1954.
  26. Schweighoffer E, Vanes L, Mathiot A, et al. Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. Immunity 2003; 18:523.
  27. Cossman J, Neckers LM, Arnold A, Korsmeyer SJ. Induction of differentiation in a case of common acute lymphoblastic leukemia. N Engl J Med 1982; 307:1251.
  28. Nadler LM, Ritz J, Bates MP, et al. Induction of human B cell antigens in non-T cell acute lymphoblastic leukemia. J Clin Invest 1982; 70:433.
  29. Shipp MA, Richardson NE, Sayre PH, et al. Molecular cloning of the common acute lymphoblastic leukemia antigen (CALLA) identifies a type II integral membrane protein. Proc Natl Acad Sci U S A 1988; 85:4819.
  30. Shipp MA, Vijayaraghavan J, Schmidt EV, et al. Common acute lymphoblastic leukemia antigen (CALLA) is active neutral endopeptidase 24.11 ("enkephalinase"): direct evidence by cDNA transfection analysis. Proc Natl Acad Sci U S A 1989; 86:297.
  31. Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today 1994; 15:450.
  32. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005; 8:140.
  33. Hemler ME. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol 1990; 8:365.
  34. Ryan DH, Nuccie BL, Abboud CN, Winslow JM. Vascular cell adhesion molecule-1 and the integrin VLA-4 mediate adhesion of human B cell precursors to cultured bone marrow adherent cells. J Clin Invest 1991; 88:995.
  35. Durie FH, Foy TM, Masters SR, et al. The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol Today 1994; 15:406.
  36. Armitage RJ, Fanslow WC, Strockbine L, et al. Molecular and biological characterization of a murine ligand for CD40. Nature 1992; 357:80.
  37. Nitschke L, Tsubata T. Molecular interactions regulate BCR signal inhibition by CD22 and CD72. Trends Immunol 2004; 25:543.
  38. van Zelm MC, van der Burg M, Langerak AW, van Dongen JJ. PID comes full circle: applications of V(D)J recombination excision circles in research, diagnostics and newborn screening of primary immunodeficiency disorders. Front Immunol 2011; 2:12.
  39. Tussiwand R, Bosco N, Ceredig R, Rolink AG. Tolerance checkpoints in B-cell development: Johnny B good. Eur J Immunol 2009; 39:2317.
  41. Gallatin WM, Weissman IL, Butcher EC. A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature 1983; 304:30.
  42. Goldstein LA, Zhou DF, Picker LJ, et al. A human lymphocyte homing receptor, the hermes antigen, is related to cartilage proteoglycan core and link proteins. Cell 1989; 56:1063.
  43. St John T, Meyer J, Idzerda R, Gallatin WM. Expression of CD44 confers a new adhesive phenotype on transfected cells. Cell 1990; 60:45.
  44. Stamenkovic I, Amiot M, Pesando JM, Seed B. A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell 1989; 56:1057.
  45. Stoolman LM. Adhesion molecules controlling lymphocyte migration. Cell 1989; 56:907.
  46. Tedder TF, Penta AC, Levine HB, Freedman AS. Expression of the human leukocyte adhesion molecule, LAM1. Identity with the TQ1 and Leu-8 differentiation antigens. J Immunol 1990; 144:532.
  47. Spertini O, Freedman AS, Belvin MP, et al. Regulation of leukocyte adhesion molecule-1 (TQ1, Leu-8) expression and shedding by normal and malignant cells. Leukemia 1991; 5:300.
  48. Siegelman MH, van de Rijn M, Weissman IL. Mouse lymph node homing receptor cDNA clone encodes a glycoprotein revealing tandem interaction domains. Science 1989; 243:1165.
  49. Springer TA. Adhesion receptors of the immune system. Nature 1990; 346:425.
  50. Astier AL, Xu R, Svoboda M, et al. Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival. Blood 2003; 101:1118.
  51. Kuijpers TW, Bende RJ, Baars PA, et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest 2010; 120:214.
  52. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008; 111:3941.
  53. Carroll MC. The role of complement in B cell activation and tolerance. Adv Immunol 2000; 74:61.
  54. Freedman AS, Munro JM, Rice GE, et al. Adhesion of human B cells to germinal centers in vitro involves VLA-4 and INCAM-110. Science 1990; 249:1030.
  55. Li L, Zhang X, Kovacic S, et al. Identification of a human follicular dendritic cell molecule that stimulates germinal center B cell growth. J Exp Med 2000; 191:1077.
  56. Grammer AC, Slota R, Fischer R, et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J Clin Invest 2003; 112:1506.
  57. Van de Velde H, von Hoegen I, Luo W, et al. The B-cell surface protein CD72/Lyb-2 is the ligand for CD5. Nature 1991; 351:662.
  58. Bikah G, Carey J, Ciallella JR, et al. CD5-mediated negative regulation of antigen receptor-induced growth signals in B-1 B cells. Science 1996; 274:1906.
  59. Youinou P, Jamin C, Lydyard PM. CD5 expression in human B-cell populations. Immunol Today 1999; 20:312.
  60. Nisitani S, Murakami M, Akamizu T, et al. Preferential localization of human CD5+ B cells in the peritoneal cavity. Scand J Immunol 1997; 46:541.
  61. Bofill M, Janossy G, Janossa M, et al. Human B cell development. II. Subpopulations in the human fetus. J Immunol 1985; 134:1531.
  62. Hannet I, Erkeller-Yuksel F, Lydyard P, et al. Developmental and maturational changes in human blood lymphocyte subpopulations. Immunol Today 1992; 13:215, 218.
  63. Lydyard PM, Quartey-Papafio R, Bröker B, et al. The antibody repertoire of early human B cells. I. High frequency of autoreactivity and polyreactivity. Scand J Immunol 1990; 31:33.
  64. Chen ZJ, Wheeler J, Notkins AL. Antigen-binding B cells and polyreactive antibodies. Eur J Immunol 1995; 25:579.
  65. Casali P, Notkins AL. Probing the human B-cell repertoire with EBV: polyreactive antibodies and CD5+ B lymphocytes. Annu Rev Immunol 1989; 7:513.
  66. Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 2010; 10:778.
  67. Chou MY, Fogelstrand L, Hartvigsen K, et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest 2009; 119:1335.
  68. Ueki Y, Goldfarb IS, Harindranath N, et al. Clonal analysis of a human antibody response. Quantitation of precursors of antibody-producing cells and generation and characterization of monoclonal IgM, IgG, and IgA to rabies virus. J Exp Med 1990; 171:19.
  69. Clark EA, Ledbetter JA. Structure, function, and genetics of human B cell-associated surface molecules. Adv Cancer Res 1989; 52:81.
  70. Gordon J. B-cell signalling via the C-type lectins CD23 and CD72. Immunol Today 1994; 15:411.
  71. Stokes J, Casale TB. Rationale for new treatments aimed at IgE immunomodulation. Ann Allergy Asthma Immunol 2004; 93:212.
  72. Nurieva RI, Liu X, Dong C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev 2009; 229:88.
  73. Liu M, Duke JL, Richter DJ, et al. Two levels of protection for the B cell genome during somatic hypermutation. Nature 2008; 451:841.
  74. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 2009; 15:5494.
  75. Islam KB, Nilsson L, Sideras P, et al. TGF-beta 1 induces germ-line transcripts of both IgA subclasses in human B lymphocytes. Int Immunol 1991; 3:1099.
  76. Durandy A, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev 2005; 203:67.
  77. Uckun FM. Regulation of human B-cell ontogeny. Blood 1990; 76:1908.
  78. Oracki SA, Walker JA, Hibbs ML, et al. Plasma cell development and survival. Immunol Rev 2010; 237:140.
  79. Nutt SL, Fairfax KA, Kallies A. BLIMP1 guides the fate of effector B and T cells. Nat Rev Immunol 2007; 7:923.
  80. Hu CC, Dougan SK, McGehee AM, et al. XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells. EMBO J 2009; 28:1624.
  81. Schuber F, Lund FE. Structure and enzymology of ADP-ribosyl cyclases: conserved enzymes that produce multiple calcium mobilizing metabolites. Curr Mol Med 2004; 4:249.
  82. Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol 2015; 15:149.
  83. Gray D. Immunological memory: a function of antigen persistence. Trends Microbiol 1993; 1:39.
  84. Wehr C, Kivioja T, Schmitt C, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 2008; 111:77.
  85. van de Ven AA, van de Corput L, van Tilburg CM, et al. Lymphocyte characteristics in children with common variable immunodeficiency. Clin Immunol 2010; 135:63.
  86. Yu VW, Saez B, Cook C, et al. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med 2015; 212:759.
  87. Pace KE, Hahn HP, Pang M, et al. CD7 delivers a pro-apoptotic signal during galectin-1-induced T cell death. J Immunol 2000; 165:2331.
  88. Krause DS, Fackler MJ, Civin CI, May WS. CD34: structure, biology, and clinical utility. Blood 1996; 87:1.
  89. Bodey B, Bodey B Jr, Siegel SE, Kaiser HE. Molecular biological ontogenesis of the thymic reticulo-epithelial cell network during the organization of the cellular microenvironment. In Vivo 1999; 13:267.
  90. Hadden JW. Thymic endocrinology. Ann N Y Acad Sci 1998; 840:352.
  91. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 2006; 441:988.
  92. Bleul CC, Corbeaux T, Reuter A, et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 2006; 441:992.
  93. Radtke F, Fasnacht N, Macdonald HR. Notch signaling in the immune system. Immunity 2010; 32:14.
  94. Schüler T, Hämmerling GJ, Arnold B. Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells. J Immunol 2004; 172:15.
  95. Puel A, Leonard WJ. Mutations in the gene for the IL-7 receptor result in T(-)B(+)NK(+) severe combined immunodeficiency disease. Curr Opin Immunol 2000; 12:468.
  96. Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 2009; 9:833.
  97. Singh VK, Biswas S, Mathur KB, et al. Thymopentin and splenopentin as immunomodulators. Current status. Immunol Res 1998; 17:345.
  98. Haks MC, Oosterwegel MA, Blom B, et al. Cell-fate decisions in early T cell development: regulation by cytokine receptors and the pre-TCR. Semin Immunol 1999; 11:23.
  99. Anderson G, Harman BC, Hare KJ, Jenkinson EJ. Microenvironmental regulation of T cell development in the thymus. Semin Immunol 2000; 12:457.
  100. Ulrichs T, Porcelli SA. CD1 proteins: targets of T cell recognition in innate and adaptive immunity. Rev Immunogenet 2000; 2:416.
  101. Dimitroff CJ, Lee JY, Rafii S, et al. CD44 is a major E-selectin ligand on human hematopoietic progenitor cells. J Cell Biol 2001; 153:1277.
  102. Gaffen SL. Signaling domains of the interleukin 2 receptor. Cytokine 2001; 14:63.
  103. Dadi HK, Simon AJ, Roifman CM. Effect of CD3delta deficiency on maturation of alpha/beta and gamma/delta T-cell lineages in severe combined immunodeficiency. N Engl J Med 2003; 349:1821.
  104. Irving BA, Alt FW, Killeen N. Thymocyte development in the absence of pre-T cell receptor extracellular immunoglobulin domains. Science 1998; 280:905.
  105. Richmond J, Tuzova M, Cruikshank W, Center D. Regulation of cellular processes by interleukin-16 in homeostasis and cancer. J Cell Physiol 2014; 229:139.
  106. Hayday AC. [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 2000; 18:975.
  107. Nikolich-Zugich J, Slifka MK, Messaoudi I. The many important facets of T-cell repertoire diversity. Nat Rev Immunol 2004; 4:123.
  108. von Boehmer H, Aifantis I, Azogui O, et al. The impact of pre-T-cell receptor signals on gene expression in developing T cells. Cold Spring Harb Symp Quant Biol 1999; 64:283.
  109. Palmer E. Negative selection--clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol 2003; 3:383.
  110. Ye P, Kirschner DE. Measuring emigration of human thymocytes by T-cell receptor excision circles. Crit Rev Immunol 2002; 22:483.
  111. van den Dool C, de Boer RJ. The effects of age, thymectomy, and HIV Infection on alpha and beta TCR excision circles in naive T cells. J Immunol 2006; 177:4391.
  112. Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol 2012; 129:607.
  113. Lewis JM, Girardi M, Roberts SJ, et al. Selection of the cutaneous intraepithelial gammadelta+ T cell repertoire by a thymic stromal determinant. Nat Immunol 2006; 7:843.
  114. Prezzi C, Casciaro MA, Francavilla V, et al. Virus-specific CD8(+) T cells with type 1 or type 2 cytokine profile are related to different disease activity in chronic hepatitis C virus infection. Eur J Immunol 2001; 31:894.
  115. Tsuji-Yamada J, Nakazawa M, Minami M, Sasaki T. Increased frequency of interleukin 4 producing CD4+ and CD8+ cells in peripheral blood from patients with systemic sclerosis. J Rheumatol 2001; 28:1252.
  116. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4:330.
  117. Albert MH, Anasetti C, Yu XZ. T regulatory cells as an immunotherapy for transplantation. Expert Opin Biol Ther 2006; 6:315.
  118. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011; 29:621.
  119. Fasnacht N, Huang HY, Koch U, et al. Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. J Exp Med 2014; 211:2265.
  120. Purwar R, Schlapbach C, Xiao S, et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 2012; 18:1248.
  121. Weaver CT, Harrington LE, Mangan PR, et al. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006; 24:677.
  122. Furuzawa-Carballeda J, Vargas-Rojas MI, Cabral AR. Autoimmune inflammation from the Th17 perspective. Autoimmun Rev 2007; 6:169.
  123. de Latour RP, Visconte V, Takaku T, et al. Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood 2010; 116:4175.
  124. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007; 8:942.
  125. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8:950.
  126. Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol Int 2008; 57:121.
  127. Amin K, Lúdvíksdóttir D, Janson C, et al. Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group. Am J Respir Crit Care Med 2000; 162:2295.
  128. McDonald DR. TH17 deficiency in human disease. J Allergy Clin Immunol 2012; 129:1429.
  129. Perniola R, Lobreglio G, Rosatelli MC, et al. Immunophenotypic characterisation of peripheral blood lymphocytes in autoimmune polyglandular syndrome type 1: clinical study and review of the literature. J Pediatr Endocrinol Metab 2005; 18:155.