Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


The development of immune cells in the fetus and neonate

INTRODUCTION

This topic review will address the development of the different cells of the immune system in fetal and neonatal life and review what is known about how these cells differ in function from adult cells. More general descriptions relating to the development of these cells are presented separately. (See "Normal B and T lymphocyte development".)

The clinical consequences of the altered functioning of the neonatal immune system, specifically in relation to infections and laboratory testing, are reviewed separately. (See "Immunity of the newborn".)

T CELLS

T cell development — The thymus arises from the third branchial arch at about six weeks of gestation, with the cortex arising from its ectodermal layer and the medulla from the endoderm. Lymphoid cells migrate over the next two to three weeks, initially from the yolk sac and fetal liver, and then from the bone marrow to colonize the fetal thymus [1,2].

These prothymocytes interact with the stroma, proliferate actively, and are triggered to differentiate with expression of the first T cell-specific surface molecules (eg, CD2 and later, CD4 and CD8) [3]. A clear delineation of the thymic cortical and medullary regions occurs at 12 weeks of gestation. Hassall's corpuscles appear shortly thereafter [4]. The most immature thymocytes are found in the subcapsular cortical region, and cells move into the deeper layers as they mature [5].

The early prothymocytes do not express CD3, the T cell receptor (TCR), CD4, or CD8 and are often referred to as "triple-negative thymocytes" [6]. The progeny continue to divide and rearrange their TCR genes, and since these cells express both CD4 and CD8, they are now called "double-positive" cells [6,7]. They undergo positive selection by self-major histocompatibility complex (MHC) restriction. More than 95 percent (nearly 50 million) of the cells die each day during this stage [6].

                               

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2014. | This topic last updated: Jul 9, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Holt PG, Jones CA. The development of the immune system during pregnancy and early life. Allergy 2000; 55:688.
  2. Crompton T, Outram SV, Hager-Theodorides AL. Sonic hedgehog signalling in T-cell development and activation. Nat Rev Immunol 2007; 7:726.
  3. Anderson G, Moore NC, Owen JJ, Jenkinson EJ. Cellular interactions in thymocyte development. Annu Rev Immunol 1996; 14:73.
  4. Bodey B, Kaiser HE. Development of Hassall's bodies of the thymus in humans and other vertebrates (especially mammals) under physiological and pathological conditions: immunocytochemical, electronmicroscopic and in vitro observations. In Vivo 1997; 11:61.
  5. Bodey B, Bodey B Jr, Siegel SE, Kaiser HE. Novel insights into the function of the thymic Hassall's bodies. In Vivo 2000; 14:407.
  6. Mathieson BJ, Fowlkes BJ. Cell surface antigen expression on thymocytes: development and phenotypic differentiation of intrathymic subsets. Immunol Rev 1984; 82:141.
  7. Kraft DL, Weissman IL, Waller EK. Differentiation of CD3-4-8- human fetal thymocytes in vivo: characterization of a CD3-4+8- intermediate. J Exp Med 1993; 178:265.
  8. Chidgey AP, Boyd RL. Thymic stromal cells and positive selection. APMIS 2001; 109:481.
  9. Viret C, Janeway CA Jr. MHC and T cell development. Rev Immunogenet 1999; 1:91.
  10. Haynes BF. The human thymic microenvironment. Adv Immunol 1984; 36:87.
  11. George JF Jr, Schroeder HW Jr. Developmental regulation of D beta reading frame and junctional diversity in T cell receptor-beta transcripts from human thymus. J Immunol 1992; 148:1230.
  12. Teyton L, Apostolopoulos V, Cantu C 3rd, et al. Function and dysfunction of T cell receptor: structural studies. Immunol Res 2000; 21:325.
  13. Garcia KC, Degano M, Speir JA, Wilson IA. Emerging principles for T cell receptor recognition of antigen in cellular immunity. Rev Immunogenet 1999; 1:75.
  14. Hazenberg MD, Verschuren MC, Hamann D, et al. T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J Mol Med (Berl) 2001; 79:631.
  15. Jouvin-Marche E, Fuschiotti P, Marche PN. Dynamic aspects of TCRalpha gene recombination: qualitative and quantitative assessments of the TCRalpha chain repertoire in man and mouse. Adv Exp Med Biol 2009; 650:82.
  16. Davis MM, Bjorkman PJ. T-cell antigen receptor genes and T-cell recognition. Nature 1988; 334:395.
  17. Schelonka RL, Raaphorst FM, Infante D, et al. T cell receptor repertoire diversity and clonal expansion in human neonates. Pediatr Res 1998; 43:396.
  18. Bonati A, Zanelli P, Ferrari S, et al. T-cell receptor beta-chain gene rearrangement and expression during human thymic ontogenesis. Blood 1992; 79:1472.
  19. Garderet L, Dulphy N, Douay C, et al. The umbilical cord blood alphabeta T-cell repertoire: characteristics of a polyclonal and naive but completely formed repertoire. Blood 1998; 91:340.
  20. Zemlin M, Schelonka RL, Bauer K, Schroeder HW Jr. Regulation and chance in the ontogeny of B and T cell antigen receptor repertoires. Immunol Res 2002; 26:265.
  21. Erkeller-Yuksel FM, Deneys V, Yuksel B, et al. Age-related changes in human blood lymphocyte subpopulations. J Pediatr 1992; 120:216.
  22. Panaro A, Amati A, di Loreto M, et al. Lymphocyte subpopulations in pediatric age. Definition of reference values by flow cytometry. Allergol Immunopathol (Madr) 1991; 19:109.
  23. Gasparoni A, Ciardelli L, Avanzini A, et al. Age-related changes in intracellular TH1/TH2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns, children and adults. Biol Neonate 2003; 84:297.
  24. Thilaganathan B, Mansur CA, Morgan G, Nicolaides KH. Fetal T-lymphocyte subpopulations in normal pregnancies. Fetal Diagn Ther 1992; 7:53.
  25. Sériès IM, Pichette J, Carrier C, et al. Quantitative analysis of T and B cell subsets in healthy and sick premature infants. Early Hum Dev 1991; 26:143.
  26. Wilson M, Rosen FS, Schlossman SF, Reinherz EL. Ontogeny of human T and B lymphocytes during stressed and normal gestation: phenotypic analysis of umbilical cord lymphocytes from term and preterm infants. Clin Immunol Immunopathol 1985; 37:1.
  27. Pirenne H, Aujard Y, Eljaafari A, et al. Comparison of T cell functional changes during childhood with the ontogeny of CDw29 and CD45RA expression on CD4+ T cells. Pediatr Res 1992; 32:81.
  28. Hassan J, Reen DJ. Neonatal CD4+ CD45RA+ T cells: precursors of adult CD4+ CD45RA+ T cells? Res Immunol 1993; 144:87.
  29. Hoshino T, Yamada A, Honda J, et al. Tissue-specific distribution and age-dependent increase of human CD11b+ T cells. J Immunol 1993; 151:2237.
  30. Splawski JB, Jelinek DF, Lipsky PE. Delineation of the functional capacity of human neonatal lymphocytes. J Clin Invest 1991; 87:545.
  31. Schaub B, Liu J, Schleich I, et al. Impairment of T helper and T regulatory cell responses at birth. Allergy 2008; 63:1438.
  32. Roncarolo MG, Bigler M, Ciuti E, et al. Immune responses by cord blood cells. Blood Cells 1994; 20:573.
  33. Reen DJ, Early E. Cord blood 'naive' T cells demonstrate distinct immunological properties compared with their adult counterparts. Bone Marrow Transplant 1998; 22 Suppl 1:S35.
  34. Risdon G, Gaddy J, Stehman FB, Broxmeyer HE. Proliferative and cytotoxic responses of human cord blood T lymphocytes following allogeneic stimulation. Cell Immunol 1994; 154:14.
  35. Clerici M, DePalma L, Roilides E, et al. Analysis of T helper and antigen-presenting cell functions in cord blood and peripheral blood leukocytes from healthy children of different ages. J Clin Invest 1993; 91:2829.
  36. Liechty KW, Adzick NS, Crombleholme TM. Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair. Cytokine 2000; 12:671.
  37. Müller K, Zak M, Nielsen S, et al. In vitro cytokine production and phenotype expression by blood mononuclear cells from umbilical cords, children and adults. Pediatr Allergy Immunol 1996; 7:117.
  38. Sautois B, Fillet G, Beguin Y. Comparative cytokine production by in vitro stimulated mononucleated cells from cord blood and adult blood. Exp Hematol 1997; 25:103.
  39. Qian JX, Lee SM, Suen Y, et al. Decreased interleukin-15 from activated cord versus adult peripheral blood mononuclear cells and the effect of interleukin-15 in upregulating antitumor immune activity and cytokine production in cord blood. Blood 1997; 90:3106.
  40. Lilic D, Cant AJ, Abinun M, et al. Cytokine production differs in children and adults. Pediatr Res 1997; 42:237.
  41. Seghaye MC, Heyl W, Grabitz RG, et al. The production of pro- and anti-inflammatory cytokines in neonates assessed by stimulated whole cord blood culture and by plasma levels at birth. Biol Neonate 1998; 73:220.
  42. Chheda S, Palkowetz KH, Garofalo R, et al. Decreased interleukin-10 production by neonatal monocytes and T cells: relationship to decreased production and expression of tumor necrosis factor-alpha and its receptors. Pediatr Res 1996; 40:475.
  43. Chang M, Suen Y, Lee SM, et al. Transforming growth factor-beta 1, macrophage inflammatory protein-1 alpha, and interleukin-8 gene expression is lower in stimulated human neonatal compared with adult mononuclear cells. Blood 1994; 84:118.
  44. Pirenne-Ansart H, Paillard F, De Groote D, et al. Defective cytokine expression but adult-type T-cell receptor, CD8, and p56lck modulation in CD3- or CD2-activated T cells from neonates. Pediatr Res 1995; 37:64.
  45. Cairo MS, Suen Y, Knoppel E, et al. Decreased stimulated GM-CSF production and GM-CSF gene expression but normal numbers of GM-CSF receptors in human term newborns compared with adults. Pediatr Res 1991; 30:362.
  46. White GP, Watt PM, Holt BJ, Holt PG. Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differences in IFN-gamma gene expression between human neonatal and adult CD45RO- T cells. J Immunol 2002; 168:2820.
  47. Gromo G, Geller RL, Inverardi L, Bach FH. Signal requirements in the step-wise functional maturation of cytotoxic T lymphocytes. Nature 1987; 327:424.
  48. Steele CR, Oppenheim DE, Hayday AC. Gamma(delta) T cells: non-classical ligands for non-classical cells. Curr Biol 2000; 10:R282.
  49. Beetz S, Wesch D, Marischen L, et al. Innate immune functions of human gammadelta T cells. Immunobiology 2008; 213:173.
  50. McVay LD, Carding SR. Extrathymic origin of human gamma delta T cells during fetal development. J Immunol 1996; 157:2873.
  51. Holtmeier W, Pfänder M, Hennemann A, et al. The TCR-delta repertoire in normal human skin is restricted and distinct from the TCR-delta repertoire in the peripheral blood. J Invest Dermatol 2001; 116:275.
  52. Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136:2348.
  53. Adkins B. Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally. J Immunol 2003; 171:5157.
  54. Delespesse G, Yang LP, Ohshima Y, et al. Maturation of human neonatal CD4+ and CD8+ T lymphocytes into Th1/Th2 effectors. Vaccine 1998; 16:1415.
  55. Weaver CT, Harrington LE, Mangan PR, et al. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006; 24:677.
  56. Ivanov S, Bozinovski S, Bossios A, et al. Functional relevance of the IL-23-IL-17 axis in lungs in vivo. Am J Respir Cell Mol Biol 2007; 36:442.
  57. Cosmi L, De Palma R, Santarlasci V, et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med 2008; 205:1903.
  58. 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.
  59. Takahashi N, Imanishi K, Nishida H, Uchiyama T. Evidence for immunologic immaturity of cord blood T cells. Cord blood T cells are susceptible to tolerance induction to in vitro stimulation with a superantigen. J Immunol 1995; 155:5213.
  60. Toubert A, Douay C, Chalumeau N, et al. Effects of superantigenic stimulation on the cord blood alphabeta T cell repertoire. Bone Marrow Transplant 1998; 22 Suppl 1:S36.
  61. Macardle PJ, Wheatland L, Zola H. Analysis of the cord blood T lymphocyte response to superantigen. Hum Immunol 1999; 60:127.
  62. Liu CC, Young LH, Young JD. Lymphocyte-mediated cytolysis and disease. N Engl J Med 1996; 335:1651.
  63. Kägi D, Ledermann B, Bürki K, et al. Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annu Rev Immunol 1996; 14:207.
  64. Smyth MJ, Kelly JM, Sutton VR, et al. Unlocking the secrets of cytotoxic granule proteins. J Leukoc Biol 2001; 70:18.
  65. Toivanen P, Uksila J, Leino A, et al. Development of mitogen responding T cells and natural killer cells in the human fetus. Immunol Rev 1981; 57:89.
  66. Lubens RG, Gard SE, Soderberg-Warner M, Stiehm ER. Lectin-dependent T-lymphocyte and natural killer cytotoxic deficiencies in human newborns. Cell Immunol 1982; 74:40.
  67. Peakman M, Buggins AG, Nicolaides KH, et al. Analysis of lymphocyte phenotypes in cord blood from early gestation fetuses. Clin Exp Immunol 1992; 90:345.
  68. McVay LD, Carding SR. Generation of human gammadelta T-cell repertoires. Crit Rev Immunol 1999; 19:431.
  69. Yamashita S, Tanaka Y, Harazaki M, et al. Recognition mechanism of non-peptide antigens by human gammadelta T cells. Int Immunol 2003; 15:1301.
  70. Hintz M, Reichenberg A, Altincicek B, et al. Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. FEBS Lett 2001; 509:317.
  71. Morita CT, Parker CM, Brenner MB, Band H. TCR usage and functional capabilities of human gamma delta T cells at birth. J Immunol 1994; 153:3979.
  72. Sloan-Lancaster J, Allen PM. Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu Rev Immunol 1996; 14:1.
  73. Groux H, O'Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389:737.
  74. Barrat FJ, Cua DJ, Boonstra A, et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002; 195:603.
  75. Darrasse-Jèze G, Marodon G, Salomon BL, et al. Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses. Blood 2005; 105:4715.
  76. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057.
  77. Allman D, Miller JP. Common lymphoid progenitors, early B-lineage precursors, and IL-7: characterizing the trophic and instructive signals underlying early B cell development. Immunol Res 2003; 27:131.
  78. Nagasawa T. Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol 2006; 6:107.
  79. Klein M. Immunological markers of human mononuclear cells. Clin Biochem 1983; 16:128.
  80. Nossal GJ. The Florey lecture, 1986. The regulatory biology of antibody formation. Proc R Soc Lond B Biol Sci 1986; 228:225.
  81. Buhl AM, Nemazee D, Cambier JC, et al. B-cell antigen receptor competence regulates B-lymphocyte selection and survival. Immunol Rev 2000; 176:141.
  82. Rudin CM, Thompson CB. B-cell development and maturation. Semin Oncol 1998; 25:435.
  83. Pillai S, Cariappa A, Moran ST. Marginal zone B cells. Annu Rev Immunol 2005; 23:161.
  84. Bofill M, Janossy G, Janossa M, et al. Human B cell development. II. Subpopulations in the human fetus. J Immunol 1985; 134:1531.
  85. Dorshkind K, Montecino-Rodriguez E. Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential. Nat Rev Immunol 2007; 7:213.
  86. Oltz EM. Regulation of antigen receptor gene assembly in lymphocytes. Immunol Res 2001; 23:121.
  87. Kelsoe G. V(D)J hypermutation and receptor revision: coloring outside the lines. Curr Opin Immunol 1999; 11:70.
  88. Neuberger MS, Di Noia JM, Beale RC, et al. Somatic hypermutation at A.T pairs: polymerase error versus dUTP incorporation. Nat Rev Immunol 2005; 5:171.
  89. Casali P, Schettino EW. Structure and function of natural antibodies. Curr Top Microbiol Immunol 1996; 210:167.
  90. Schroeder HW Jr, Hillson JL, Perlmutter RM. Early restriction of the human antibody repertoire. Science 1987; 238:791.
  91. Choi Y, Rickert MH, Ballow M, Greenberg SJ. Human IgH-V gene repertoire in neonatal cord blood, adult peripheral blood, and EBV-transformed cells. Ann N Y Acad Sci 1995; 764:261.
  92. Ridings J, Nicholson IC, Goldsworthy W, et al. Somatic hypermutation of immunoglobulin genes in human neonates. Clin Exp Immunol 1997; 108:366.
  93. Paloczi K. Immunophenotypic and functional characterization of human umbilical cord blood mononuclear cells. Leukemia 1999; 13 Suppl 1:S87.
  94. Ugazio AG, Marcioni AF, Astaldi A Jr, Burgio GR. Peripheral blood B lymphocytes in infancy and childhood. Acta Paediatr Scand 1974; 63:205.
  95. Thomas RM, Linch DC. Identification of lymphocyte subsets in the newborn using a variety of monoclonal antibodies. Arch Dis Child 1983; 58:34.
  96. Durandy A, Thuillier L, Forveille M, Fischer A. Phenotypic and functional characteristics of human newborns' B lymphocytes. J Immunol 1990; 144:60.
  97. Johnson CC, Ownby DR, Peterson EL. Parental history of atopic disease and concentration of cord blood IgE. Clin Exp Allergy 1996; 26:624.
  98. King CL, Malhotra I, Mungai P, et al. B cell sensitization to helminthic infection develops in utero in humans. J Immunol 1998; 160:3578.
  99. D'Angio CT, Maniscalco WM, Pichichero ME. Immunologic response of extremely premature infants to tetanus, Haemophilus influenzae, and polio immunizations. Pediatrics 1995; 96:18.
  100. Gołebiowska M, Kardas-Sobantka D, Chlebna-Sokół D, Sabanty W. Hepatitis B vaccination in preterm infants. Eur J Pediatr 1999; 158:293.
  101. Palfi M, Hildén JO, Gottvall T, Selbing A. Placental transport of maternal immunoglobulin G in pregnancies at risk of Rh (D) hemolytic disease of the newborn. Am J Reprod Immunol 1998; 39:323.
  102. Ballow M, Cates KL, Rowe JC, et al. Development of the immune system in very low birth weight (less than 1500 g) premature infants: concentrations of plasma immunoglobulins and patterns of infections. Pediatr Res 1986; 20:899.
  103. Yeung CY, Hobbs JR. Serum-gamma-G-globulin levels in normal premature, post-mature, and "small-for-dates" newborn babies. Lancet 1968; 1:1167.
  104. Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest 2007; 117:712.
  105. Deorari AK, Broor S, Maitreyi RS, et al. Incidence, clinical spectrum, and outcome of intrauterine infections in neonates. J Trop Pediatr 2000; 46:155.
  106. Karras JG, Wang Z, Huo L, et al. Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, self-renewing B-1 cells but only inducibly expressed in conventional B lymphocytes. J Exp Med 1997; 185:1035.
  107. Hardy RR. B-1 B cell development. J Immunol 2006; 177:2749.
  108. Montecino-Rodriguez E, Dorshkind K. New perspectives in B-1 B cell development and function. Trends Immunol 2006; 27:428.
  109. Kantor AB, Herzenberg LA. Origin of murine B cell lineages. Annu Rev Immunol 1993; 11:501.
  110. Bhat NM, Kantor AB, Bieber MM, et al. The ontogeny and functional characteristics of human B-1 (CD5+ B) cells. Int Immunol 1992; 4:243.
  111. Hardy RR, Hayakawa K. A developmental switch in B lymphopoiesis. Proc Natl Acad Sci U S A 1991; 88:11550.
  112. Alugupalli KR, Leong JM, Woodland RT, et al. B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity 2004; 21:379.
  113. Haas KM, Poe JC, Steeber DA, Tedder TF. B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity 2005; 23:7.
  114. Bishop GA, Hostager BS. B lymphocyte activation by contact-mediated interactions with T lymphocytes. Curr Opin Immunol 2001; 13:278.
  115. Nonoyama S, Etzioni A, Toru H, et al. Diminished expression of CD40 ligand may contribute to the defective humoral immunity in patients with MHC class II deficiency. Eur J Immunol 1998; 28:589.
  116. Merrill JD, Sigaroudinia M, Kohl S. Characterization of natural killer and antibody-dependent cellular cytotoxicity of preterm infants against human immunodeficiency virus-infected cells. Pediatr Res 1996; 40:498.
  117. Splawski JB, Nishioka J, Nishioka Y, Lipsky PE. CD40 ligand is expressed and functional on activated neonatal T cells. J Immunol 1996; 156:119.
  118. Fehniger TA, Caligiuri MA. Ontogeny and expansion of human natural killer cells: clinical implications. Int Rev Immunol 2001; 20:503.
  119. Spits H, Blom B, Jaleco AC, et al. Early stages in the development of human T, natural killer and thymic dendritic cells. Immunol Rev 1998; 165:75.
  120. Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet 1998; 20:394.
  121. Volpé R. Graves' disease/model of SCID mouse. Exp Clin Endocrinol Diabetes 1996; 104 Suppl 3:37.
  122. Phillips JH, Hori T, Nagler A, et al. Ontogeny of human natural killer (NK) cells: fetal NK cells mediate cytolytic function and express cytoplasmic CD3 epsilon,delta proteins. J Exp Med 1992; 175:1055.
  123. Gaddy J, Risdon G, Broxmeyer HE. Cord blood natural killer cells are functionally and phenotypically immature but readily respond to interleukin-2 and interleukin-12. J Interferon Cytokine Res 1995; 15:527.
  124. Trinchieri G. Biology of natural killer cells. Adv Immunol 1989; 47:187.
  125. Leibson PJ. Signal transduction during natural killer cell activation: inside the mind of a killer. Immunity 1997; 6:655.
  126. Ortaldo JR, Winkler-Pickett RT, Nagashima K, et al. Direct evidence for release of pore-forming protein during NK cellular lysis. J Leukoc Biol 1992; 52:483.
  127. Trinchieri G, Valiante N. Receptors for the Fc fragment of IgG on natural killer cells. Nat Immun 1993; 12:218.
  128. Gaunt G, Ramin K. Immunological tolerance of the human fetus. Am J Perinatol 2001; 18:299.
  129. Sato T, Laver JH, Aiba Y, Ogawa M. NK cell colony formation from human fetal thymocytes. Exp Hematol 1999; 27:726.
  130. Middendorp S, Nieuwenhuis EE. NKT cells in mucosal immunity. Mucosal Immunol 2009; 2:393.
  131. Takashina T. Haemopoiesis in the human yolk sac. J Anat 1987; 151:125.
  132. Smythies LE, Maheshwari A, Clements R, et al. Mucosal IL-8 and TGF-beta recruit blood monocytes: evidence for cross-talk between the lamina propria stroma and myeloid cells. J Leukoc Biol 2006; 80:492.
  133. Shepard JL, Zon LI. Developmental derivation of embryonic and adult macrophages. Curr Opin Hematol 2000; 7:3.
  134. Maheshwari A, Kurundkar AR, Shaik SS, et al. Epithelial cells in fetal intestine produce chemerin to recruit macrophages. Am J Physiol Gastrointest Liver Physiol 2009; 297:G1.
  135. Kelemen E, Jánossa M. Macrophages are the first differentiated blood cells formed in human embryonic liver. Exp Hematol 1980; 8:996.
  136. Janossy G, Bofill M, Poulter LW, et al. Separate ontogeny of two macrophage-like accessory cell populations in the human fetus. J Immunol 1986; 136:4354.
  137. MacDonald TT, Weinel A, Spencer J. HLA-DR expression in human fetal intestinal epithelium. Gut 1988; 29:1342.
  138. Porcellini A, Manna A, Manna M, et al. Ontogeny of granulocyte-macrophage progenitor cells in the human fetus. Int J Cell Cloning 1983; 1:92.
  139. Linch DC, Knott LJ, Rodeck CH, Huehns ER. Studies of circulating hemopoietic progenitor cells in human fetal blood. Blood 1982; 59:976.
  140. Xanthou M. Leucocyte blood picture in healthy full-term and premature babies during neonatal period. Arch Dis Child 1970; 45:242.
  141. Weinberg AG, Rosenfeld CR, Manroe BL, Browne R. Neonatal blood cell count in health and disease. II. Values for lymphocytes, monocytes, and eosinophils. J Pediatr 1985; 106:462.
  142. Christensen RD, Jensen J, Maheshwari A, Henry E. Reference ranges for blood concentrations of eosinophils and monocytes during the neonatal period defined from over 63 000 records in a multihospital health-care system. J Perinatol 2010; 30:540.
  143. Kurland G, Cheung AT, Miller ME, et al. The ontogeny of pulmonary defenses: alveolar macrophage function in neonatal and juvenile rhesus monkeys. Pediatr Res 1988; 23:293.
  144. D'Ambola JB, Sherman MP, Tashkin DP, Gong H Jr. Human and rabbit newborn lung macrophages have reduced anti-Candida activity. Pediatr Res 1988; 24:285.
  145. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18:767.
  146. Jaffe R. Review of human dendritic cells: isolation and culture from precursors. Pediatr Pathol 1993; 13:821.
  147. Foster CA, Holbrook KA, Farr AG. Ontogeny of Langerhans cells in human embryonic and fetal skin: expression of HLA-DR and OKT-6 determinants. J Invest Dermatol 1986; 86:240.
  148. Grouard G, Rissoan MC, Filgueira L, et al. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med 1997; 185:1101.
  149. O'Doherty U, Peng M, Gezelter S, et al. Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology 1994; 82:487.
  150. Velilla PA, Rugeles MT, Chougnet CA. Defective antigen-presenting cell function in human neonates. Clin Immunol 2006; 121:251.
  151. Petty RE, Hunt DW. Neonatal dendritic cells. Vaccine 1998; 16:1378.
  152. Johnston RB Jr. Current concepts: immunology. Monocytes and macrophages. N Engl J Med 1988; 318:747.
  153. Yoder MC, Lanker TA, Engle WA. Culture medium oxygen tension affects fibronectin production in human adult and cord blood macrophages. Immunol Lett 1988; 19:1.
  154. Stiehm ER, Sztein MB, Steeg PS, et al. Deficient DR antigen expression on human cord blood monocytes: reversal with lymphokines. Clin Immunol Immunopathol 1984; 30:430.
  155. Bhoopat L, Taylor CR, Hofman FM. The differentiation antigens of macrophages in human fetal liver. Clin Immunol Immunopathol 1986; 41:184.
  156. Weatherstone KB, Rich EA. Tumor necrosis factor/cachectin and interleukin-1 secretion by cord blood monocytes from premature and term neonates. Pediatr Res 1989; 25:342.
  157. Wilson CB. Immunologic basis for increased susceptibility of the neonate to infection. J Pediatr 1986; 108:1.
  158. Bessler H, Sirota L, Dulitzky F, Djaldetti M. Production of interleukin-1 by mononuclear cells of newborns and their mothers. Clin Exp Immunol 1987; 68:655.
  159. Kesson AM, Bryson YJ. Induction of interferon-gamma by cord blood mononuclear cells is calcium dependent. Cell Immunol 1991; 133:138.
  160. Kniker WT, Lesourd BM, McBryde JL, Corriel RN. Cell-mediated immunity assessed by Multitest CMI skin testing in infants and preschool children. Am J Dis Child 1985; 139:840.
  161. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol 2008; 181:3733.
  162. Schibler KR, Liechty KW, White WL, et al. Defective production of interleukin-6 by monocytes: a possible mechanism underlying several host defense deficiencies of neonates. Pediatr Res 1992; 31:18.
  163. Schibler KR, Trautman MS, Liechty KW, et al. Diminished transcription of interleukin-8 by monocytes from preterm neonates. J Leukoc Biol 1993; 53:399.
  164. Speer CP, Ambruso DR, Grimsley J, Johnston RB Jr. Oxidative metabolism in cord blood monocytes and monocyte-derived macrophages. Infect Immun 1985; 50:919.
  165. Speer CP, Wieland M, Ulbrich R, Gahr M. Phagocytic activities in neonatal monocytes. Eur J Pediatr 1986; 145:418.
  166. Weston WL, Carson BS, Barkin RM, et al. Monocyte-macrophage function in the newborn. Am J Dis Child 1977; 131:1241.
  167. Bondada S, Wu H, Robertson DA, Chelvarajan RL. Accessory cell defect in unresponsiveness of neonates and aged to polysaccharide vaccines. Vaccine 2000; 19:557.