Protecting the Newborn and Young Infant from Infectious Diseases: Lessons from Immune Ontogeny

Immunity

Volumn 46, Issue 3, 2017, Pages 350-363

  Kollmann, Tobias R ^a   Kampmann, Beate ^b   Mazmanian, Sarkis K ^c   Marchant, Arnaud ^e   Levy, Ofer ^d  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^b MEDICAL RESEARCH COUNCIL   (United Kingdom)

^c California Institute of Technology   (United States)

^d BOSTON CHILDREN S HOSPITAL   (United States)

^e UNIVERSITÉ LIBRE DE BRUXELLES   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ADAPTIVE IMMUNITY; DISEASE SEVERITY; EFFECTOR CELL; HOST RESISTANCE; HUMAN; IMMUNE SYSTEM; IMMUNOREGULATION; INFECTION SENSITIVITY; INNATE IMMUNITY; MICROBIAL COLONIZATION; NEWBORN INFECTION; NONHUMAN; ONTOGENY; PHYLOGENY; PLASTICITY; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; COMMUNICABLE DISEASE; DISEASE PREDISPOSITION; GROWTH, DEVELOPMENT AND AGING; IMMUNOLOGY; INFANT; NEWBORN;

ANIMALS; COMMUNICABLE DISEASES; DISEASE SUSCEPTIBILITY; HUMANS; IMMUNE SYSTEM; INFANT; INFANT, NEWBORN;

EID: 85015771024     PISSN: 10747613     EISSN: 10974180     Source Type: Journal    
DOI: 10.1016/j.immuni.2017.03.009     Document Type: Review

References (196)

1. Aaby, P., Kollmann, T.R., Benn, C.S., Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges. Nat. Immunol. 15 (2014), 895–899.
2. Aagaard, K., Ma, J., Antony, K.M., Ganu, R., Petrosino, J., Versalovic, J., The placenta harbors a unique microbiome. Sci. Transl. Med., 6, 2014, 237ra265.
3. Abel, L., Plancoulaine, S., Jouanguy, E., Zhang, S.Y., Mahfoufi, N., Nicolas, N., Sancho-Shimizu, V., Alcaïs, A., Guo, Y., Cardon, A., et al. Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood. J. Pediatr. 157 (2010), 623–629 629.e1.
4. Agarwal, R., Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study. The Lancet Global health, 4, 2016 e752-760.
5. AlFaleh, K., Anabrees, J., Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst. Rev., 4, 2014, CD005496.
6. Amirthalingam, G., Andrews, N., Campbell, H., Ribeiro, S., Kara, E., Donegan, K., Fry, N.K., Miller, E., Ramsay, M., Effectiveness of maternal pertussis vaccination in England: an observational study. Lancet 384 (2014), 1521–1528.
7. Ardeshir, A., Narayan, N.R., Mendez-Lagares, G., Lu, D., Rauch, M., Huang, Y., Van Rompay, K.K., Lynch, S.V., Hartigan-O'Connor, D.J., Breast-fed and bottle-fed infant rhesus macaques develop distinct gut microbiotas and immune systems. Sci Transl Med, 6, 2014, 252ra120.
8. Arrieta, M.C., Stiemsma, L.T., Amenyogbe, N., Brown, E.M., Finlay, B., The intestinal microbiome in early life: health and disease. Front. Immunol., 5, 2014, 427.
9. Arrieta, M.C., Stiemsma, L.T., Dimitriu, P.A., Thorson, L., Russell, S., Yurist-Doutsch, S., Kuzeljevic, B., Gold, M.J., Britton, H.M., Lefebvre, D.L., et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med, 7, 2015, 307ra152.
10. Bärnighausen, T., Bloom, D.E., Cafiero-Fonseca, E.T., O'Brien, J.C., Valuing vaccination. Proc. Natl. Acad. Sci. USA 111 (2014), 12313–12319.
11. Battersby, A.J., Khara, J., Wright, V.J., Levy, O., Kampmann, B., Antimicrobial Proteins and Peptides in Early Life: Ontogeny and Translational Opportunities. Front. Immunol., 7, 2016, 309.
12. Beigi, R.H., Fortner, K.B., Munoz, F.M., Roberts, J., Gordon, J.L., Han, H.H., Glenn, G., Dormitzer, P.R., Gu, X.X., Read, J.S., et al. Maternal immunization: opportunities for scientific advancement. Clin. Infect. Dis. 59:Suppl 7 (2014), S408–S414.
13. Beisel, W.R., History of nutritional immunology: introduction and overview. J. Nutr. 122:3, Suppl (1992), 591–596.
14. Bertoletti, A., Hong, M., Age-Dependent Immune Events during HBV Infection from Birth to Adulthood: An Alternative Interpretation. Front. Immunol., 5, 2014, 441.
15. Bhutta, Z.A., Black, R.E., Global maternal, newborn, and child health–so near and yet so far. N. Engl. J. Med. 369 (2013), 2226–2235.
16. Blencowe, H., Vos, T., Lee, A.C., Philips, R., Lozano, R., Alvarado, M.R., Cousens, S., Lawn, J.E., Estimates of neonatal morbidities and disabilities at regional and global levels for 2010: introduction, methods overview, and relevant findings from the Global Burden of Disease study. Pediatr. Res. 74:Suppl 1 (2013), 4–16.
17. Boer, M.C., Joosten, S.A., Ottenhoff, T.H., Regulatory T-Cells at the Interface between Human Host and Pathogens in Infectious Diseases and Vaccination. Front Immunol, 6:217, 2015.
18. Buchmann, K., Evolution of Innate Immunity: Clues from Invertebrates via Fish to Mammals. Front. Immunol., 5, 2014, 459.
19. Buck, M.D., O'Sullivan, D., Pearce, E.L., T cell metabolism drives immunity. J Exp Med 212 (2015), 1345–1360.
20. Buffen, K., Oosting, M., Quintin, J., Ng, A., Kleinnijenhuis, J., Kumar, V., van de Vosse, E., Wijmenga, C., van Crevel, R., Oosterwijk, E., et al. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog., 10, 2014, e1004485.
21. Buffie, C.G., Pamer, E.G., Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol 13 (2013), 790–801.
22. Bullen, J., Griffiths, E., Rogers, H., Ward, G., Sepsis: the critical role of iron. Microbes and infection 2 (2000), 409–415.
23. Carr, R., Neutrophil production and function in newborn infants. Br. J. Haematol. 110 (2000), 18–28.
24. Casanova, J.L., Abel, L., Quintana-Murci, L., Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu. Rev. Immunol. 29 (2011), 447–491.
25. Chan, M., Lake, A., Towards ending preventable child deaths. Lancet 379 (2012), 2119–2120.
26. Chan, A.C., Leeansyah, E., Cochrane, A., d'Udekem d'Acoz, Y., Mittag, D., Harrison, L.C., Godfrey, D.I., Berzins, S.P., Ex-vivo analysis of human natural killer T cells demonstrates heterogeneity between tissues and within established CD4(+) and CD4(-) subsets. Clin Exp Immunol 172 (2013), 129–137.
27. Cheng, S.C., Joosten, L.A., Netea, M.G., The interplay between central metabolism and innate immune responses. Cytokine Growth Factor Rev. 25 (2014), 707–713.
28. Chirico, G., Marconi, M., De Amici, M., Gasparoni, A., Mingrat, G., Chiara, A., Rondini, G., Ugazio, A.G., Deficiency of neutrophil bactericidal activity in term and preterm infants. A longitudinal study. Biol. Neonate 47 (1985), 125–129.
29. Chu, H., Mazmanian, S.K., Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat. Immunol. 14 (2013), 668–675.
30. Clark, N.M., Lynch, J.P. 3rd, Influenza: epidemiology, clinical features, therapy, and prevention. Semin. Respir. Crit. Care Med. 32 (2011), 373–392.
31. Clemens, J., Holmgren, J., Kaufmann, S.H., Mantovani, A., Ten years of the Global Alliance for Vaccines and Immunization: challenges and progress. Nat. Immunol. 11 (2010), 1069–1072.
32. Cox, L.M., Yamanishi, S., Sohn, J., Alekseyenko, A.V., Leung, J.M., Cho, I., Kim, S.G., Li, H., Gao, Z., Mahana, D., et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158 (2014), 705–721.
33. Cuervo, A.M., Macian, F., Autophagy, nutrition and immunology. Mol Aspects Med 33 (2012), 2–13.
34. Curtis, N., Potential role for BCG in treatment of autoimmune diseases. BMJ, 355, 2016, i6091.
35. Danis, B., George, T.C., Goriely, S., Dutta, B., Renneson, J., Gatto, L., Fitzgerald-Bocarsly, P., Marchant, A., Goldman, M., Willems, F., De Wit, D., Interferon regulatory factor 7-mediated responses are defective in cord blood plasmacytoid dendritic cells. Eur. J. Immunol. 38 (2008), 507–517.
36. Darmstadt, G.L., Kinney, M.V., Chopra, M., Cousens, S., Kak, L., Paul, V.K., Martines, J., Bhutta, Z.A., Lawn, J.E., Lancet Every Newborn Study Group. Who has been caring for the baby?. Lancet 384 (2014), 174–188.
37. Dauby, N., Goetghebuer, T., Kollmann, T.R., Levy, J., Marchant, A., Uninfected but not unaffected: chronic maternal infections during pregnancy, fetal immunity, and susceptibility to postnatal infections. Lancet Infect. Dis. 12 (2012), 330–340.
38. de Castro, M.J., Pardo-Seco, J., Martinon-Torres, F., Nonspecific (Heterologous) Protection of Neonatal BCG Vaccination Against Hospitalization Due to Respiratory Infection and Sepsis. Clin Infect Dis 60 (2015), 1611–1619.
39. De Kleer, I., Willems, F., Lambrecht, B., Goriely, S., Ontogeny of myeloid cells. Front. Immunol., 5, 2014, 423.
40. Debock, I., Flamand, V., Unbalanced Neonatal CD4(+) T-Cell Immunity. Front. Immunol., 5, 2014, 393.
41. Denkel, L.A., Schwab, F., Geffers, C., Gastmeier, P., Garten, L., Piening, B., Probiotics prevent necrotizing enterocolitis, sepsis and mortality in preterm infants: a multicenter analysis of more than 10,000 VLBW infants in German NICUs. Antimicrob. Resist. Infect. Control, 4, 2015, O39.
42. Deshmukh, H.S., Liu, Y., Menkiti, O.R., Mei, J., Dai, N., O'Leary, C.E., Oliver, P.M., Kolls, J.K., Weiser, J.N., Worthen, G.S., The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med 20 (2014), 524–530.
43. Di Bartolomeo, S., Nazio, F., Cecconi, F., The role of autophagy during development in higher eukaryotes. Traffic 11 (2010), 1280–1289.
44. Diamond, G., Legarda, D., Ryan, L.K., The innate immune response of the respiratory epithelium. Immunol. Rev. 173 (2000), 27–38.
45. Dimova, T., Brouwer, M., Gosselin, F., Tassignon, J., Leo, O., Donner, C., Marchant, A., Vermijlen, D., Effector Vgamma9Vdelta2 T cells dominate the human fetal gammadelta T-cell repertoire. Proc Natl Acad Sci USA, 112, 2015 E556-565.
46. Dominguez-Bello, M.G., Blaser, M.J., Asthma: Undoing millions of years of coevolution in early life?. Sci Transl Med, 7, 2015, 307fs339.
47. Dorrestein, P.C., Mazmanian, S.K., Knight, R., Finding the missing links among metabolites, microbes, and the host. Immunity 40 (2014), 824–832.
48. Dorschner, R.A., Lin, K.H., Murakami, M., Gallo, R.L., Neonatal skin in mice and humans expresses increased levels of antimicrobial peptides: innate immunity during development of the adaptive response. Pediatr. Res. 53 (2003), 566–572.
49. Dowling, D.J., Levy, O., Ontogeny of early life immunity. Trends Immunol. 35 (2014), 299–310.
50. Elahi, S., New insight into an old concept: role of immature erythroid cells in immune pathogenesis of neonatal infection. Front Immunol, 5, 2014, 376.
51. Elahi, S., Buchanan, R.M., Attah-Poku, S., Townsend, H.G., Babiuk, L.A., Gerdts, V., The host defense peptide beta-defensin 1 confers protection against Bordetella pertussis in newborn piglets. Infect. Immun. 74 (2006), 2338–2352.
52. Elahi, S., Ertelt, J.M., Kinder, J.M., Jiang, T.T., Zhang, X., Xin, L., Chaturvedi, V., Strong, B.S., Qualls, J.E., Steinbrecher, K.A., et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504 (2013), 158–162.
53. Fink, P.J., The biology of recent thymic emigrants. Annu Rev Immunol 31 (2013), 31–50.
54. Gantt, S., Muller, W.J., The immunologic basis for severe neonatal herpes disease and potential strategies for therapeutic intervention. Clin. Dev. Immunol., 2013, 2013, 369172.
55. Gantt, S., Gervassi, A., Jaspan, H., Horton, H., The role of myeloid-derived suppressor cells in immune ontogeny. Front. Immunol., 5, 2014, 387.
56. Garcia-Vidal, C., Viasus, D., Carratalà, J., Pathogenesis of invasive fungal infections. Curr. Opin. Infect. Dis. 26 (2013), 270–276.
57. Gervassi, A., Lejarcegui, N., Dross, S., Jacobson, A., Itaya, G., Kidzeru, E., Gantt, S., Jaspan, H., Horton, H., Myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro T cell responses. PLoS One, 9, 2014, e107816.
58. Ghazal, P., Dickinson, P., Smith, C.L., Early life response to infection. Curr. Opin. Infect. Dis. 26 (2013), 213–218.
59. Gomez de Agüero, M., Ganal-Vonarburg, S.C., Fuhrer, T., Rupp, S., Uchimura, Y., Li, H., Steinert, A., Heikenwalder, M., Hapfelmeier, S., Sauer, U., et al. The maternal microbiota drives early postnatal innate immune development. Science 351 (2016), 1296–1302.
60. Gomez-Lopez, N., StLouis, D., Lehr, M.A., Sanchez-Rodriguez, E.N., Arenas-Hernandez, M., Immune cells in term and preterm labor. Cell. Mol. Immunol. 11 (2014), 571–581.
61. Goodridge, H.S., Ahmed, S.S., Curtis, N., Kollmann, T.R., Levy, O., Netea, M.G., Pollard, A.J., van Crevel, R., Wilson, C.B., Harnessing the beneficial heterologous effects of vaccination. Nature Reviews Immunology 16 (2016), 392–400.
62. Hackam, D.J., Afrazi, A., Good, M., Sodhi, C.P., Innate immune signaling in the pathogenesis of necrotizing enterocolitis. Clin. Dev. Immunol., 2013, 2013, 475415.
63. Haines, C.J., Giffon, T.D., Lu, L.S., Lu, X., Tessier-Lavigne, M., Ross, D.T., Lewis, D.B., Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. J Exp Med 206 (2009), 275–285.
64. Halsey, N., Galazka, A., The efficacy of DPT and oral poliomyelitis immunization schedules initiated from birth to 12 weeks of age. Bull. World Health Organ. 63 (1985), 1151–1169.
65. Hanson, L.A., Korotkova, M., The role of breastfeeding in prevention of neonatal infection. Seminars in neonatology 7 (2002), 275–281.
66. Haskó, G., Cronstein, B., Regulation of inflammation by adenosine. Front. Immunol., 4, 2013, 85.
67. Hay, G., Refsum, H., Whitelaw, A., Melbye, E.L., Haug, E., Borch-Iohnsen, B., Predictors of serum ferritin and serum soluble transferrin receptor in newborns and their associations with iron status during the first 2 y of life. Am. J. Clin. Nutr. 86 (2007), 64–73.
68. Hermann, E., Truyens, C., Alonso-Vega, C., Even, J., Rodriguez, P., Berthe, A., Gonzalez-Merino, E., Torrico, F., Carlier, Y., Human fetuses are able to mount an adultlike CD8 T-cell response. Blood 100 (2002), 2153–2158.
69. Hong, D.K., and Lewis, D.B. (2015). Developmental Immunology and Role of Host Defenses in Fetal and Neonatal Susceptibility to Infection. In Infectious Diseases of the Fetus and Newborn Infant, V.N. Christopher B Wilson, Yvonne Maldonado, Jack S Remington, Jerome O Klein, ed. (Philiadelphia: Elsevier Saunders), pp. 81–188.
70. Hood, M.I., Skaar, E.P., Nutritional immunity: transition metals at the pathogen-host interface. Nat. Rev. Microbiol. 10 (2012), 525–537.
71. Hornef, M.W., Fulde, M., Ontogeny of intestinal epithelial innate immune responses. Front. Immunol., 5, 2014, 474.
72. Hostetter, M.K., What we don't see. N. Engl. J. Med. 366 (2012), 1328–1334.
73. Hsieh, E., Smith, P.B., Jacqz-Aigrain, E., Kaguelidou, F., Cohen-Wolkowiez, M., Manzoni, P., Benjamin, D.K. Jr., Neonatal fungal infections: when to treat?. Early Hum. Dev. 88:Suppl 2 (2012), S6–S10.
74. Huda, M.N., Lewis, Z., Kalanetra, K.M., Rashid, M., Ahmad, S.M., Raqib, R., Qadri, F., Underwood, M.A., Mills, D.A., Stephensen, C.B., Stool microbiota and vaccine responses of infants. Pediatrics 134 (2014), e362–e372.
75. Huygens, A., Lecomte, S., Tackoen, M., Olislagers, V., Delmarcelle, Y., Burny, W., Van Rysselberge, M., Liesnard, C., Larsen, M., Appay, V., et al. Functional Exhaustion Limits CD4+ and CD8+ T-Cell Responses to Congenital Cytomegalovirus Infection. J Infect Dis 212 (2015), 484–494.
76. Iwasaki, A., Medzhitov, R., Control of adaptive immunity by the innate immune system. Nat Immunol 16 (2015), 343–353.
77. Johnson, E.E., Wessling-Resnick, M., Iron metabolism and the innate immune response to infection. Microbes and infection 14 (2012), 207–216.
78. Jones, S.A., Directing transition from innate to acquired immunity: defining a role for IL-6. J. Immunol. 175 (2005), 3463–3468.
79. Khosravi, A., Yanez, A., Price, J.G., Chow, A., Merad, M., Goodridge, H.S., Mazmanian, S.K., Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15 (2014), 374–381.
80. Kinder, J.M., Jiang, T.T., Ertelt, J.M., Xin, L., Strong, B.S., Shaaban, A.F., Way, S.S., Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells. Cell 162 (2015), 505–515.
81. King, A.E., Kelly, R.W., Sallenave, J.M., Bocking, A.D., Challis, J.R., Innate immune defences in the human uterus during pregnancy. Placenta 28 (2007), 1099–1106.
82. Kleinnijenhuis, J., Quintin, J., Preijers, F., Benn, C.S., Joosten, L.A., Jacobs, C., van Loenhout, J., Xavier, R.J., Aaby, P., van der Meer, J.W., et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J. Innate Immun. 6 (2014), 152–158.
83. Kleinnijenhuis, J., van Crevel, R., Netea, M.G., Trained immunity: consequences for the heterologous effects of BCG vaccination. Trans. R. Soc. Trop. Med. Hyg. 109 (2015), 29–35.
84. Kochan, I., Golden, C.A., Bukovic, J.A., Mechanism of tuberculostasis in mammalian serum. II. Induction of serum tuberculostasis in guinea pigs. J. Bacteriol. 100 (1969), 64–70.
85. Koff, W.C., Schenkelberg, T., Decoding the human immune system to transform the future of global disease prevention and control. Expert Rev. Vaccines 15 (2016), 1235–1236.
86. Kollmann, T.R., Levy, O., Montgomery, R.R., Goriely, S., Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37 (2012), 771–783.
87. Krow-Lucal, E.R., McCune, J.M., Distinct functional programs in fetal T and myeloid lineages. Front. Immunol., 5, 2014, 314.
88. Landwehr-Kenzel, S., Henneke, P., Interaction of Streptococcus agalactiae and Cellular Innate Immunity in Colonization and Disease. Front. Immunol., 5, 2014, 519.
89. Lawn, J.E., Blencowe, H., Oza, S., You, D., Lee, A.C., Waiswa, P., Lalli, M., Bhutta, Z., Barros, A.J., Christian, P., et al., Lancet Every Newborn Study Group. Every Newborn: progress, priorities, and potential beyond survival. Lancet 384 (2014), 189–205.
90. Legrand, D., Overview of Lactoferrin as a Natural Immune Modulator. J. Pediatr. 173:Suppl (2016), S10–S15.
91. Lemoine, S., Jaron, B., Tabka, S., Ettreiki, C., Deriaud, E., Zhivaki, D., Le Ray, C., Launay, O., Majlessi, L., Tissieres, P., et al. Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells. The Journal of allergy and clinical immunology 136 (2015), 1355–1368.
92. Levine, M.M., “IDEAL” vaccines for resource poor settings. Vaccine 29:Suppl 4 (2011), D116–D125.
93. Levy, O., Innate immunity of the newborn: basic mechanisms and clinical correlates. Nature reviews 7 (2007), 379–390.
94. Levy, O., Netea, M.G., Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines. Pediatr. Res. 75 (2014), 184–188.
95. Levy, O., Coughlin, M., Cronstein, B.N., Roy, R.M., Desai, A., Wessels, M.R., The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J. Immunol. 177 (2006), 1956–1966.
96. Li, Q., Shen, H.H., Neonatal bacillus Calmette-Guérin vaccination inhibits de novo allergic inflammatory response in mice via alteration of CD4+CD25+ T-regulatory cells. Acta Pharmacol. Sin. 30 (2009), 125–133.
97. Liang, Q., Luo, Z., Zeng, J., Chen, W., Foo, S.S., Lee, S.A., Ge, J., Wang, S., Goldman, S.A., Zlokovic, B.V., et al. Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell 19 (2016), 663–671.
98. Libraty, D.H., Zhang, L., Woda, M., Acosta, L.P., Obcena, A., Brion, J.D., Capeding, R.Z., Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines. Trials Vaccinol. 3 (2014), 1–5.
99. Lindsey, B., Jones, C., Kampmann, B., Bridging the gap: maternal immunisation as a means to reduce neonatal deaths from infectious diseases. Pathog. Glob. Health 106 (2012), 137–138.
100. Lindsey, B., Kampmann, B., Jones, C., Maternal immunization as a strategy to decrease susceptibility to infection in newborn infants. Curr. Opin. Infect. Dis. 26 (2013), 248–253.
101. Lissner, M.M., Thomas, B.J., Wee, K., Tong, A.J., Kollmann, T.R., Smale, S.T., Age-Related Gene Expression Differences in Monocytes from Human Neonates, Young Adults, and Older Adults. PLoS One, 10, 2015, e0132061.
102. Liu, L., Johnson, H.L., Cousens, S., Perin, J., Scott, S., Lawn, J.E., Rudan, I., Campbell, H., Cibulskis, R., Li, M., et al., Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379 (2012), 2151–2161.
103. Lotz, M., Gütle, D., Walther, S., Ménard, S., Bogdan, C., Hornef, M.W., Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203 (2006), 973–984.
104. Lund, N., Andersen, A., Hansen, A.S., Jepsen, F.S., Barbosa, A., Biering-Sørensen, S., Rodrigues, A., Ravn, H., Aaby, P., Benn, C.S., The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial. Clin. Infect. Dis. 61 (2015), 1504–1511.
105. MacGillivray, D.M., Kollmann, T.R., The role of environmental factors in modulating immune responses in early life. Front. Immunol., 5, 2014, 434.
106. Mansbach, J.M., Piedra, P.A., Borregaard, N., Martineau, A.R., Neuman, M.I., Espinola, J.A., Camargo, C.A. Jr., Serum cathelicidin level is associated with viral etiology and severity of bronchiolitis. J Allergy Clin Immunol 130 (2012), 1007–1008.
107. Manzoni, P., Rinaldi, M., Cattani, S., Pugni, L., Romeo, M.G., Messner, H., Stolfi, I., Decembrino, L., Laforgia, N., Vagnarelli, F., et al., Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 302 (2009), 1421–1428.
108. Manzoni, P., Stolfi, I., Messner, H., Cattani, S., Laforgia, N., Romeo, M.G., Bollani, L., Rinaldi, M., Gallo, E., Quercia, M., et al., Italian Task Force for the Study and Prevention of Neonatal Fungal Infections–the Italian Society of Neonatology. Bovine lactoferrin prevents invasive fungal infections in very low birth weight infants: a randomized controlled trial. Pediatrics 129 (2012), 116–123.
109. Manzoni, P., Meyer, M., Stolfi, I., Rinaldi, M., Cattani, S., Pugni, L., Romeo, M.G., Messner, H., Decembrino, L., Laforgia, N., et al. Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial. Early Hum. Dev. 90:Suppl 1 (2014), S60–S65.
110. Marchant, A., Goetghebuer, T., Ota, M.O., Wolfe, I., Ceesay, S.J., De Groote, D., Corrah, T., Bennett, S., Wheeler, J., Huygen, K., et al. Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guérin vaccination. J. Immunol. 163 (1999), 2249–2255.
111. Marchant, E.A., Boyce, G.K., Sadarangani, M., Lavoie, P.M., Neonatal sepsis due to coagulase-negative staphylococci. Clin. Dev. Immunol., 2013, 2013, 586076.
112. Marchant, E.A., Kan, B., Sharma, A.A., van Zanten, A., Kollmann, T.R., Brant, R., Lavoie, P.M., Attenuated innate immune defenses in very premature neonates during the neonatal period. Pediatr. Res. 78 (2015), 492–497.
113. Marchini, G., Lindow, S., Brismar, H., Ståbi, B., Berggren, V., Ulfgren, A.K., Lonne-Rahm, S., Agerberth, B., Gudmundsson, G.H., The newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa. Br. J. Dermatol. 147 (2002), 1127–1134.
114. Mascart, F., Verscheure, V., Malfroot, A., Hainaut, M., Piérard, D., Temerman, S., Peltier, A., Debrie, A.S., Levy, J., Del Giudice, G., Locht, C., Bordetella pertussis infection in 2-month-old infants promotes type 1 T cell responses. J. Immunol. 170 (2003), 1504–1509.
115. Maynard, C.L., Elson, C.O., Hatton, R.D., Weaver, C.T., Reciprocal interactions of the intestinal microbiota and immune system. Nature 489 (2012), 231–241.
116. McFall-Ngai, M., Hadfield, M.G., Bosch, T.C., Carey, H.V., Domazet-Loso, T., Douglas, A.E., Dubilier, N., Eberl, G., Fukami, T., Gilbert, S.F., et al. Animals in a bacterial world, a new imperative for the life sciences. Proc Natl Acad Sci USA 110 (2013), 3229–3236.
117. Mold, J.E., Michaelsson, J., Burt, T.D., Muench, M.O., Beckerman, K.P., Busch, M.P., Lee, T.H., Nixon, D.F., McCune, J.M., Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322 (2008), 1562–1565.
118. Mold, J.E., Venkatasubrahmanyam, S., Burt, T.D., Michaëlsson, J., Rivera, J.M., Galkina, S.A., Weinberg, K., Stoddart, C.A., McCune, J.M., Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330 (2010), 1695–1699.
119. Muenchhoff, M., Prendergast, A.J., Goulder, P.J., Immunity to HIV in Early Life. Front. Immunol., 5, 2014, 391.
120. Muenchhoff, M., Adland, E., Karimanzira, O., Crowther, C., Pace, M., Csala, A., Leitman, E., Moonsamy, A., McGregor, C., Hurst, J., et al. Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection. Sci. Transl. Med., 8, 2016, 358ra125.
121. Murray, C.J., Vos, T., Lozano, R., Naghavi, M., Flaxman, A.D., Michaud, C., Ezzati, M., Shibuya, K., Salomon, J.A., Abdalla, S., et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380 (2012), 2197–2223.
122. Nairz, M., Haschka, D., Demetz, E., Weiss, G., Iron at the interface of immunity and infection. Front. Pharmacol., 5, 2014, 152.
123. Nakazawa, T., Agematsu, K., Yabuhara, A., Later development of Fas ligand-mediated cytotoxicity as compared with granule-mediated cytotoxicity during the maturation of natural killer cells. Immunology 92 (1997), 180–187.
124. Netea, M.G., van Crevel, R., BCG-induced protection: effects on innate immune memory. Semin. Immunol. 26 (2014), 512–517.
125. Netea, M.G., Latz, E., Mills, K.H., O'Neill, L.A., Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol 16 (2015), 675–679.
126. Niewiesk, S., Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies. Front. Immunol., 5, 2014, 446.
127. O'Neill, L.A., Kishton, R.J., Rathmell, J., A guide to immunometabolism for immunologists. Nature reviews 16 (2016), 553–565.
128. Oh, J.E., Lee, H.K., Pattern recognition receptors and autophagy. Front Immunol, 5, 2014, 300.
129. Oh, J.Z., Ravindran, R., Chassaing, B., Carvalho, F.A., Maddur, M.S., Bower, M., Hakimpour, P., Gill, K.P., Nakaya, H.I., Yarovinsky, F., et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41 (2014), 478–492.
130. Oh, D.Y., Dowling, D.J., Ahmed, S., Choi, H., Brightman, S., Bergelson, I., Berger, S.T., Sauld, J.F., Pettengill, M., Kho, A.T., et al. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures. Mol. Cell. Proteomics 15 (2016), 1877–1894.
131. Olszak, T., An, D., Zeissig, S., Vera, M.P., Richter, J., Franke, A., Glickman, J.N., Siebert, R., Baron, R.M., Kasper, D.L., Blumberg, R.S., Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336 (2012), 489–493.
132. Oncel, M.Y., Sari, F.N., Arayici, S., Guzoglu, N., Erdeve, O., Uras, N., Oguz, S.S., Dilmen, U., Lactobacillus Reuteri for the prevention of necrotising enterocolitis in very low birthweight infants: a randomised controlled trial. Arch. Dis. Child. Fetal Neonatal 99 (2014), F110–F115.
133. Oppenheimer, S.J., Iron and its relation to immunity and infectious disease. The Journal of nutrition 131 (2001), 616S–633S.
134. Oppenheimer, S., Iron and infection: narrative review of a major iron supplementation study in Papua New Guinea undertaken by the Department of Tropical Paediatrics, Liverpool School of Tropical Medicine, 1979-1983, its aftermath and the continuing relevance of its results. Paediatr. Int. Child Health 32:Suppl 2 (2012), S21–S29.
135. Ota, M.O., Vekemans, J., Schlegel-Haueter, S.E., Fielding, K., Sanneh, M., Kidd, M., Newport, M.J., Aaby, P., Whittle, H., Lambert, P.H., et al. Influence of Mycobacterium bovis bacillus Calmette-Guérin on antibody and cytokine responses to human neonatal vaccination. J. Immunol. 168 (2002), 919–925.
136. Ota, M.O., Vekemans, J., Schlegel-Haueter, S.E., Fielding, K., Whittle, H., Lambert, P.H., McAdam, K.P., Siegrist, C.A., Marchant, A., Hepatitis B immunisation induces higher antibody and memory Th2 responses in new-borns than in adults. Vaccine 22 (2004), 511–519.
137. Pammi, M., Abrams, S.A., Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst. Rev., 2, 2015, CD007137, 10.1002/14651858.CD14007137.pub14651854.
138. Pandiyan, P., Zheng, L., Lenardo, M.J., The molecular mechanisms of regulatory T cell immunosuppression. Front Immunol, 2, 2011, 60.
139. Panigrahi, P. (2013). Effectiveness of a Lactbacillus plantarum synbiotic therapy for preventing late onset sepsis in neonates. Paper presented at: PAS Annual Meeting (Washington D.C.: Pediatric Academic Society).
140. Pettengill, M.A., Levy, O., Circulating Human Neonatal Naïve B Cells are Deficient in CD73 Impairing Purine Salvage. Front. Immunol., 7, 2016, 121.
141. Pettengill, M., Robson, S., Tresenriter, M., Millán, J.L., Usheva, A., Bingham, T., Belderbos, M., Bergelson, I., Burl, S., Kampmann, B., et al. Soluble ecto-5′-nucleotidase (5′-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J. Biol. Chem. 288 (2013), 27315–27326.
142. Pettengill, M.A., van Haren, S.D., Levy, O., Soluble mediators regulating immunity in early life. Front. Immunol., 5, 2014, 457.
143. Power Coombs, M.R., Kronforst, K., Levy, O., Neonatal host defense against Staphylococcal infections. Clin. Dev. Immunol., 2013, 2013, 826303.
144. Randow, F., MacMicking, J.D., James, L.C., Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 340 (2013), 701–706.
145. Rao, S., Ali, U., Systemic fungal infections in neonates. J. Postgrad. Med. 51:Suppl 1 (2005), S27–S29.
146. Recalcati, S., Locati, M., Cairo, G., Systemic and cellular consequences of macrophage control of iron metabolism. Semin. Immunol. 24 (2012), 393–398.
147. Rechavi, E., Lev, A., Lee, Y.N., Simon, A.J., Yinon, Y., Lipitz, S., Amariglio, N., Weisz, B., Notarangelo, L.D., Somech, R., Timely and spatially regulated maturation of B and T cell repertoire during human fetal development. Sci. Transl. Med., 7, 2015, 276ra25.
148. Renz, H., Brandtzaeg, P., Hornef, M., The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nature reviews 12 (2012), 9–23.
149. Richetta, C., Faure, M., Autophagy in antiviral innate immunity. Cell Microbiol 15 (2013), 368–376.
150. Rochette, L., Gudjoncik, A., Guenancia, C., Zeller, M., Cottin, Y., Vergely, C., The iron-regulatory hormone hepcidin: a possible therapeutic target?. Pharmacol. Ther. 146 (2015), 35–52.
151. Rousseau, M.C., Parent, M.E., St-Pierre, Y., Potential health effects from non-specific stimulation of the immune function in early age: the example of BCG vaccination. Pediatr. Allergy Immunol. 19 (2008), 438–448.
152. Roy, A., Chaudhuri, J., Sarkar, D., Ghosh, P., Chakraborty, S., Role of Enteric Supplementation of Probiotics on Late-onset Sepsis by Candida species in Preterm Low Birth Weight Neonates: A Randomized, Double Blind, Placebo-controlled Trial. N. Am. J. Med. Sci. 6 (2014), 50–57.
153. Ruchala, P., Nemeth, E., The pathophysiology and pharmacology of hepcidin. Trends Pharmacol. Sci. 35 (2014), 155–161.
154. Salzman, N.H., Underwood, M.A., Bevins, C.L., Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin. Immunol. 19 (2007), 70–83.
155. Samanta, M., Sarkar, M., Ghosh, P., Ghosh, Jk., Sinha, Mk., Chatterjee, S., Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. J. Trop. Pediatr. 55 (2009), 128–131.
156. Saso, A., Kampmann, B., Vaccination against respiratory syncytial virus in pregnancy: a suitable tool to combat global infant morbidity and mortality?. Lancet Infect. Dis. 16 (2016), e153–e163.
157. Sassone-Corsi, M., Raffatellu, M., No vacancy: how beneficial microbes cooperate with immunity to provide colonization resistance to pathogens. J Immunol 194 (2015), 4081–4087.
158. Sazawal, S., Black, R.E., Ramsan, M., Chwaya, H.M., Stoltzfus, R.J., Dutta, A., Dhingra, U., Kabole, I., Deb, S., Othman, M.K., Kabole, F.M., Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 367 (2006), 133–143.
159. Seale, A.C., Blencowe, H., Manu, A.A., Nair, H., Bahl, R., Qazi, S.A., Zaidi, A.K., Berkley, J.A., Cousens, S.N., Lawn, J.E., pSBI Investigator Group. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect. Dis. 14 (2014), 731–741.
160. Sepúlveda, J., Murray, C., The state of global health in 2014. Science 345 (2014), 1275–1278.
161. Sharma, A.A., Jen, R., Butler, A., Lavoie, P.M., The developing human preterm neonatal immune system: a case for more research in this area. Clin Immunol 145 (2012), 61–68.
162. Sherrid, A.M., Kollmann, T.R., Age-dependent differences in systemic and cell-autonomous immunity to L. monocytogenes. Clin. Dev. Immunol., 2013, 2013, 917198.
163. Siegrist, C.A., Aspinall, R., B-cell responses to vaccination at the extremes of age. Nature reviews 9 (2009), 185–194.
164. Singh, V.V., Chauhan, S.K., Rai, R., Kumar, A., Singh, S.M., Rai, G., Decreased pattern recognition receptor signaling, interferon-signature, and bactericidal/permeability-increasing protein gene expression in cord blood of term low birth weight human newborns. PLoS ONE, 8, 2013, e62845.
165. Sørup, S., Benn, C.S., Poulsen, A., Krause, T.G., Aaby, P., Ravn, H., Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA 311 (2014), 826–835.
166. Speer, C.P., Gahr, M., Wieland, M., Eber, S., Phagocytosis-associated functions in neonatal monocyte-derived macrophages. Pediatr. Res. 24 (1988), 213–216.
167. Starner, T.D., Agerberth, B., Gudmundsson, G.H., McCray, P.B. Jr., Expression and activity of beta-defensins and LL-37 in the developing human lung. J. Immunol. 174 (2005), 1608–1615.
168. Strunk, T., Doherty, D., Richmond, P., Simmer, K., Charles, A., Levy, O., Liyanage, K., Smith, T., Currie, A., Burgner, D., Reduced levels of antimicrobial proteins and peptides in human cord blood plasma. Arch. Dis. Child. Fetal Neonatal 94 (2009), F230–F231.
169. Strunk, T., Kollmann, T., Patole, S., Probiotics to prevent early-life infection. Lancet Infect Dis 15 (2015), 378–379.
170. Sturgeon, P., Studies of iron requirements in infante and children. I. Normal values for serum iron, copper and free erythrocyte protoporphyrin. Pediatrics 13 (1954), 107–125.
171. Szabó, M., Vásárhelyi, B., Balla, G., Szabó, T., Machay, T., Tulassay, T., Acute postnatal increase of extracellular antioxidant defence of neonates: the role of iron metabolism. Acta Paediatr. 90 (2001), 1167–1170.
172. Thome, J.J., Bickham, K.L., Ohmura, Y., Kubota, M., Matsuoka, N., Gordon, C., Granot, T., Griesemer, A., Lerner, H., Kato, T., Farber, D.L., Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat. Med. 22 (2016), 72–77.
173. Tian, Y., Kuo, C.F., Akbari, O., Ou, J.H., Maternal-Derived Hepatitis B Virus e Antigen Alters Macrophage Function in Offspring to Drive Viral Persistence after Vertical Transmission. Immunity 44 (2016), 1204–1214.
174. Tollin, M., Bergsson, G., Kai-Larsen, Y., Lengqvist, J., Sjövall, J., Griffiths, W., Skúladóttir, G.V., Haraldsson, A., Jörnvall, H., Gudmundsson, G.H., Agerberth, B., Vernix caseosa as a multi-component defence system based on polypeptides, lipids and their interactions. Cell. Mol. Life Sci. 62 (2005), 2390–2399.
175. Tourneur, E., Chassin, C., Neonatal immune adaptation of the gut and its role during infections. Clin. Dev. Immunol., 2013, 2013, 270301.
176. Travis, S.M., Conway, B.A., Zabner, J., Smith, J.J., Anderson, N.N., Singh, P.K., Greenberg, E.P., Welsh, M.J., Activity of abundant antimicrobials of the human airway. Am. J. Respir. Cell Mol. Biol. 20 (1999), 872–879.
177. Turvey, S.E., Broide, D.H., Innate immunity. J. Allergy Clin. Immunol. 125:2, Suppl 2 (2010), S24–S32.
178. Underwood, M.A., Gilbert, W.M., Sherman, M.P., Amniotic fluid: not just fetal urine anymore. Journal of perinatology 25 (2005), 341–348.
179. UNICEF (2014). IMMUNIZATION SUMMARY - A statistical reference containing data through 2013, U.N.C.s.F. (UNICEF), ed. (New York, NY: UNICEF).
180. van Haren, S.D., Dowling, D.J., Foppen, W., Christensen, D., Andersen, P., Reed, S.G., Hershberg, R.M., Baden, L.R., Levy, O., Age-Specific Adjuvant Synergy: Dual TLR7/8 and Mincle Activation of Human Newborn Dendritic Cells Enables Th1 Polarization. J. Immunol. 197 (2016), 4413–4424.
181. van Haren, S.D., Ganapathi, L., Bergelson, I., Dowling, D.J., Banks, M., Samuels, R.C., Reed, S.G., Marshall, J.D., Levy, O., In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant. Cytokine 83 (2016), 99–109.
182. Vanden Driessche, K., Persson, A., Marais, B.J., Fink, P.J., Urdahl, K.B., Immune vulnerability of infants to tuberculosis. Clin. Dev. Immunol., 2013, 2013, 781320.
183. Vergnano, S., Sharland, M., Kazembe, P., Mwansambo, C., Heath, P.T., Neonatal sepsis: an international perspective. Archives of disease in childhood Fetal and neonatal edition 90, F220-224. Vermijlen, D., Brouwer, M., Donner, C., Liesnard, C., Tackoen, M., Van Rysselberge, M., Twite, N., Goldman, M., Marchant, A., and Willems, F. Human cytomegalovirus elicits fetal gammadelta T cell responses in utero. J. Exp. Med. 207 (2005), 807–821.
184. Vermijlen, D., Prinz, I., Ontogeny of Innate T Lymphocytes - Some Innate Lymphocytes are More Innate than Others. Front. Immunol., 5, 2014, 486.
185. Vidarsson, G., Dekkers, G., Rispens, T., IgG subclasses and allotypes: from structure to effector functions. Front Immunol, 5, 2014, 520.
186. Visscher, M., Narendran, V., The Ontogeny of Skin. Adv. Wound Care (New Rochelle) 3 (2014), 291–303.
187. Wander, K., Shell-Duncan, B., McDade, T.W., Evaluation of iron deficiency as a nutritional adaptation to infectious disease: an evolutionary medicine perspective. American journal of human biology: the official journal of the Human Biology Council 21 (2009), 172–179.
188. Weiner, J. 3rd, Kaufmann, S.H., Recent advances towards tuberculosis control: vaccines and biomarkers. J. Intern. Med. 275 (2014), 467–480.
189. White, G.P., Watt, P.M., Holt, B.J., Holt, P.G., 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. 168 (2002), 2820–2827.
190. White, G.P., Hollams, E.M., Yerkovich, S.T., Bosco, A., Holt, B.J., Bassami, M.R., Kusel, M., Sly, P.D., Holt, P.G., CpG methylation patterns in the IFNgamma promoter in naive T cells: variations during Th1 and Th2 differentiation and between atopics and non-atopics. Pediatr. Allergy Immunol. 17 (2006), 557–564.
191. Wiesner, J., Vilcinskas, A., Antimicrobial peptides: the ancient arm of the human immune system. Virulence 1 (2010), 440–464.
192. Wilcox, D.R., Wadhwani, N.R., Longnecker, R., Muller, W.J., Differential reliance on autophagy for protection from HSV encephalitis between newborns and adults. PLoS Pathog, 11, 2015, e1004580.
193. Wu, J., Chen, Z.J., Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32 (2014), 461–488.
194. Wynn, J.L., Scumpia, P.O., Stocks, B.T., Romano-Keeler, J., Alrifai, M.W., Liu, J.H., Kim, A.S., Alford, C.E., Matta, P., Weitkamp, J.H., et al. Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality. J Immunol 195 (2015), 1064–1070.
195. Yoshio, H., Tollin, M., Gudmundsson, G.H., Lagercrantz, H., Jornvall, H., Marchini, G., Agerberth, B., Antimicrobial polypeptides of human vernix caseosa and amniotic fluid: implications for newborn innate defense. Pediatr. Res. 53 (2003), 211–216.
196. Zhang, X., Mozeleski, B., Lemoine, S., Deriaud, E., Lim, A., Zhivaki, D., Azria, E., Le Ray, C., Roguet, G., Launay, O., et al. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus. Sci Transl Med, 6, 2014, 238ra272.