Skip to main content Accessibility help
  • Print publication year: 2020
  • Online publication date: October 2019

Chapter 21 - Fetal Infections: Immune Response to Infections during Fetal Life

from Fetal Infections


In humans the immune system develops early during fetal life, most immune cells being detectable by mid-gestation. This early developmental process prepares the fetus for the challenge of controlling a large diversity of infectious pathogens at birth while establishing regulated interactions with non-pathogenic commensals. Following congenital infections with viruses, bacteria, or protozoa, the fetal immune system is challenged to generate antimicrobial effector functions. The immune system of the fetus has long been considered as non-reactive or prone to tolerance to foreign antigens. Recent clinical studies have demonstrated that immune effector functions can develop during fetal life. This chapter first provides an overview of the immune system and describes current knowledge of its development during fetal life. The capacity of the fetal immune system to respond to infectious pathogens is then summarized, focusing on the most studied congenital infections.

[1]O’Shea, JJ, Paul, WE. Mechanisms Underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010; 327: 1098–102.
[2]Billingham, RE, Brent, L, Medawar, PB. Actively acquired tolerance of foreign cells. Nature. 1953; 172: 603–6.
[3]Adkins, B, Leclerc, C, Marshall-Clarke, S. Neonatal adaptive immunity comes of age. Nat Rev Immunol. 2004; 4: 553–64.
[4]Sarzotti, M, Robbins, DS, Hoffman, PM. Induction of protective CTL responses in newborn mice by a murine retrovirus. Science. 1996; 271: 1726–8.
[5]Ridge, JP, Fuchs, EJ, Matzinger, P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science. 1996; 271: 1723–6.
[6]Forsthuber, T, Yip, HC, Lehmann, PV. Induction of TH1 and TH2 immunity in neonatal mice. Science. 1996; 271: 1728–30.
[7]Marchant, A, Goldman, M. T cell-mediated immune responses in human newborns: ready to learn? Clin Exp Immunol. 2005; 141: 1018.
[8]Tavian, M, Péault, B. Embryonic development of the human hematopoietic system. Int J Dev Biol. 2005; 49: 243–50.
[9]Hong, DK, Lewis, DB. Developmental Immunology and Role of Host Defenses in Fetal and Neonatal Susceptibility to Infection. In Remington and Klein’s Infectious Diseases of the Fetus and Newborn Infant, 8th edn. Philadelphia: Elsevier Saunders, 2016, pp. 90197.
[10]Willems, F, Vollstedt, S, Suter, M. Phenotype and function of neonatal DC. Eur J Immunol. 2009; 39: 2635.
[11]Lemoine, S, Jaron, B, Tabka, S, Ettreiki, C, Deriaud, E, Zhivaki, D, et al. Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells. J Allergy Clin Immunol. 2015; 136: 13551368. e15.
[12]Salio, M, Dulphy, N, Renneson, J, Herbert, M, McMichael, A, Marchant, A, et al. Efficient priming of antigen-specific cytotoxic T lymphocytes by human cord blood dendritic cells. Int Immunol. 2003; 15: 1265–73.
[13]Rechavi, E, Somech, R. Survival of the fetus: fetal B and T cell receptor repertoire development. Semin Immunopathol. 2017; 39: 577–83.
[14]White, GP, Watt, PM, Holt, BJ, Holt, PG. Differential patterns of methylation of the IFN-promoter at CpG and non-CpG sites underlie differences in IFN-gene expression between human neonatal and adult CD45RO-T cells. J Immunol. 2002; 168: 2820–7.
[15]Zhang, X, Mozeleski, B, Lemoine, S, Deriaud, E, Lim, A, Zhivaki, D, et al. CD4 T Cells with effector memory phenotype and function develop in the sterile environment of the fetus. Sci Transl Med. 2014; 6: 238ra72.
[16]Rechavi, E, Lev, A, Lee, YN, Simon, AJ, Yinon, Y, Lipitz, S, et al. Timely and spatially regulated maturation of B and T cell repertoire during human fetal development. Sci Transl Med. 2015; 7: 276ra25.
[17]Suryani, S, Fulcher, DA, Santner-Nanan, B, Nanan, R, Wong, M, Shaw, PJ, et al. Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood. 2010; 115: 519–29.
[18]Griffin, DO, Holodick, NE, Rothstein, TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70-. J Exp Med. 2011; 208: 6780.
[19]Vermijlen, D, Prinz, I. Ontogeny of Innate T lymphocytes – some innate lymphocytes are more innate than others. Front Immunol. 2014; 5: 486.
[20]Dimova, T, Brouwer, M, Gosselin, F, Tassignon, J, Leo, O, Donner, C, et al. Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire. Proc Natl Acad Sci. 2015; 112: E556–65.
[21]Michaëlsson, J, Mold, JE, McCune, JM, Nixon, DF. Regulation of T cell responses in the developing human fetus. J Immunol. 2006; 176: 5741–8.
[22]Mold, JE, Michaëlsson, J, Burt, TD, Muench, MO, Beckerman, KP, Busch, MP, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008; 322: 1562–5.
[23]Morand, A, Zandotti, C, Charrel, R, Minodier, P, Fabre, A, Chabrol, B, et al. De TORCH à TORCHZ: fœtopathies infectieuses à virus Zika et autres. Arch Pédiatrie. 2017; 24: 911–13.
[24]Maldonado, YA, Nizet, V, Klein, JO, Remington, JS, Wilson, CB. Current concepts of infections of the fetus and newborn infant. In Remington and Klein’s Infectious Diseases of the Fetus and Newborn Infant, 8th edn. Philadelphia: Elsevier Saunders, 2016, pp. 323.
[25]Renneson, J, Dutta, B, Goriely, S, Danis, B, Lecomte, S, Laes, J-F, et al. IL-12 and type I IFN response of neonatal myeloid DC to human CMV infection. Eur J Immunol. 2009; 39: 2789–99.
[26]Marchant, A, Appay, V, van der Sande, M, Dulphy, N, Liesnard, C, Kidd, M, et al. Mature CD8+ T lymphocyte response to viral infection during fetal life. J Clin Invest. 2003; 111: 1747–55.
[27]Pédron, B, Guérin, V, Jacquemard, F, Munier, A, Daffos, F, Thulliez, P, et al. Comparison of CD8+ T cell responses to cytomegalovirus between human fetuses and their transmitter mothers. J Infect Dis. 2007; 196: 1033–43.
[28]Gibson, L, Piccinini, G, Lilleri, D, Revello, MG, Wang, Z, Markel, S, et al. Human cytomegalovirus proteins pp65 and immediate early protein 1 are common targets for CD8+ T cell responses in children with congenital or postnatal human cytomegalovirus infection. J Immunol. 2004; 172: 2256–64.
[29]Miles, DJC, van der Sande, M, Jeffries, D, Kaye, S, Ismaili, J, Ojuola, O, et al. Cytomegalovirus infection in Gambian infants leads to profound CD8 T-cell differentiation. J Virol. 2007; 81: 5766–76.
[30]Gibson, L, Dooley, S, Trzmielina, S, Somasundaran, M, Fisher, D, Revello, MG, et al. Cytomegalovirus (CMV) IE1‐ and pp65‐specific CD8+ T cell responses broaden over time after primary CMV infection in infants. J Infect Dis. 2007; 195: 1789–98.
[31]Pass, RF, Stagno, S, Britt, WJ, Alford, CA. Specific cell-mediated immunity and the natural history of congenital infection with cytomegalovirus. J Infect Dis. 1983; 148: 953–61.
[32]Starr, SE, Tolpin, MD, Friedman, HM, Paucker, K, Plotkin, SA. Impaired Cellular immunity to cytomegalovirus in congenitally infected children and their mothers. J Infect Dis. 1979; 140: 500–5.
[33]Huygens, A, Lecomte, S, Tackoen, M, Olislagers, V, Delmarcelle, Y, Burny, W, et al. Functional exhaustion limits CD4+ and CD8+ T-cell responses to congenital cytomegalovirus infection. J Infect Dis. 2015; 212: 484–94.
[34]Tu, W, Chen, S, Sharp, M, Dekker, C, Manganello, AM, Tongson, EC, et al. Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children. J Immunol. 2004; 172: 3260–7.
[35]Vermijlen, D, Brouwer, M, Donner, C, Liesnard, C, Tackoen, M, Van Rysselberge, M, et al. Human cytomegalovirus elicits fetal γδ T cell responses in utero. J Exp Med. 2010; 207: 807–21.
[36]Brizić, I, Hiršl, L, Britt, WJ, Krmpotić, A, Jonjić, S. Immune responses to congenital cytomegalovirus infection. Microbes Infect. 2017; 20: 543–51.
[37]Rovito, R, Korndewal, MJ, van Zelm, MC, Ziagkos, D, Wessels, E, van der Burg, M, et al. T and B cell markers in dried blood spots of neonates with congenital cytomegalovirus infection: B cell numbers at birth are associated with long-term outcomes. J Immunol. 2017; 198: 102–9.
[38]Huygens, A, Dauby, N, Vermijlen, D, Marchant, A. Immunity to cytomegalovirus in early life. Front Immunol. 2014; 5: 552.
[39]Noyola, DE, Fortuny, C, Muntasell, A, Noguera-Julian, A, Muñoz-Almagro, C, Alarcón, A, et al. Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK-cell subset distribution in children: immunity to infection. Eur J Immunol. 2012; 42: 3256–66.
[40]Shetty, A, Maldonado, YA. Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in the Infant. In Remington and Klein’s Infectious Diseases of the Fetus and Newborn Infant, 8th edn. Philadelphia: Elsevier Saunders, 2016, pp. 623–78.
[41]Luzuriaga, K, Holmes, D, Hereema, A, Wong, J, Panicali, DL, Sullivan, JL. HIV-1-specific cytotoxic T lymphocyte responses in the first year of life. J Immunol. 1995; 154: 433–43.
[42]Thobakgale, CF, Ramduth, D, Reddy, S, Mkhwanazi, N, de Pierres, C, Moodley, E, et al. Human immunodeficiency virus-specific CD8+ T-cell activity is detectable from birth in the majority of in utero-infected infants. J Virol. 2007; 81: 12775–84.
[43]Lohman, BL, Slyker, JA, Richardson, BA, Farquhar, C, Mabuka, JM, Crudder, C, et al. Longitudinal assessment of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon responses during the first year of life in HIV-1-infected infants. J Virol. 2005; 79: 8121–30.
[44]Streeck, H, Nixon, DF. T cell immunity in acute HIV‐1 infection. J Infect Dis. 2010; 202: S302–8.
[45]Voelkerding, KV, Sandhaus, LM, Belov, L, Frenkel, L, Ettinger, LJ, Raska, K. Clonal B-cell proliferation in an infant with congenital HIV infection and immune thrombocytopenia. Am J Clin Pathol. 1988; 90: 470–4.
[46]Pugatch, D, Sullivan, JL, Pikora, CA, Luzuriaga, K. Delayed generation of antibodies mediating human immunodeficiency virus type 1-specific antibody-dependent cellular cytotoxicity in vertically infected infants. WITS Study Group. Women and Infants Transmission Study. J Infect Dis. 1997; 176: 643–8.
[47]Munoz, M, Liesenfeld, O, Heimesaat, MM. Immunology of Toxoplasma gondii. Immunol Rev. 2011; 240: 269–85.
[48]Fatoohi, AF, Cozon, GJN, Wallon, M, Kahi, S, Gay-Andrieu, F, Greenland, T, et al. Cellular immunity to Toxoplasma gondii in congenitally infected newborns and immunocompetent infected hosts. Eur J Clin Microbiol Infect Dis. 2003; 22: 181–4.
[49]Ciardelli, L, Meroni, V, Avanzini, MA, Bollani, L, Tinelli, C, Garofoli, F, et al. Early and accurate diagnosis of congenital toxoplasmosis. Pediatr Infect Dis J. 2008; 27: 125–9.
[50]Chapey, E, Wallon, M, Debize, G, Rabilloud, M, Peyron, F. Diagnosis of congenital toxoplasmosis by using a whole-blood gamma interferon release assay. J Clin Microbiol. 2010; 48: 41–5.
[51]Guglietta, S, Beghetto, E, Spadoni, A, Buffolano, W, Del Porto, P, Gargano, N. Age-dependent impairment of functional helper T cell responses to immunodominant epitopes of Toxoplasma gondii antigens in congenitally infected individuals. Microbes Infect. 2007; 9: 127–33.
[52]McLeod, R, Mack, DG, Boyer, K, Mets, M, Roizen, N, Swisher, C, et al. Phenotypes and functions of lymphocytes in congenital toxoplasmosis. J Lab Clin Med. 1990; 116: 623–35.
[53]Hara, T, Ohashi, S, Yamashita, Y, Abe, T, Hisaeda, H, Himeno, K, et al. Human V delta 2+ gamma delta T-cell tolerance to foreign antigens of Toxoplasma gondii. Proc Natl Acad Sci U S A. 1996; 93: 5136–40.
[54]Carlier, Y, Truyens, C. Maternal–fetal transmission of Trypanosoma cruzi. In American Trypanosomiasis: Chagas Disease, 2nd edn. Amsterdam: Elsevier, 2017, pp. 517–59.
[55]Hermann, E, Truyens, C, Alonso-Vega, C, Even, J, Rodriguez, P, Berthe, A, et al. Human fetuses are able to mount an adultlike CD8 T-cell response. Blood. 2002; 100: 2153–8.
[56]Hermann, E, Alonso-Vega, C, Berthe, A, Truyens, C, Flores, A, Cordova, M, et al. Human congenital infection with Trypanosoma cruzi induces phenotypic and functional modifications of cord blood NK cells. Pediatr Res. 2006; 60: 3843.
[57]Rodriguez, P, Truyens, C, Alonso-Vega, C, Flores, A, Cordova, M, Suarez, E, et al. Serum levels for IgM and IgA antibodies to anti-trypanosoma cruzi in samples of blood from newborns from mothers with positive serology for Chagas disease. Rev Soc Bras Med Trop. 2005; 38 (Suppl. 2): 62–4.
[58]Baud, D, Gubler, DJ, Schaub, B, Lanteri, MC, Musso, D. An update on Zika virus infection. Lancet. 2017; 390: 2099–109.
[59]Weisblum, Y, Oiknine-Djian, E, Vorontsov, OM, Haimov-Kochman, R, Zakay-Rones, Z, Meir, K, et al. Zika Virus infects early- and midgestation human maternal decidual tissues, inducing distinct innate tissue responses in the maternal-fetal interface. J Virol. 2017; 91: e01905–16.
[60]Yockey, LJ, Jurado, KA, Arora, N, Millet, A, Rakib, T, Milano, KM, et al. Type I interferons instigate fetal demise after Zika virus infection. Sci Immunol. 2018; 3: eaao1680.
[61]Nem de Oliveira Souza, I, Frost, PS, França, JV, Nascimento-Viana, JB, Neris, RLS, Freitas, L, et al. Acute and chronic neurological consequences of early-life Zika virus infection in mice. Sci Transl Med. 2018; 10: eaar2749.
[62]Dauby, N, Goetghebuer, T, Kollmann, TR, Levy, J, Marchant, A. Uninfected but not unaffected: chronic maternal infections during pregnancy, fetal immunity, and susceptibility to postnatal infections. Lancet Infect Dis. 2012; 12: 330–40.
[63]Abu Raya, B, Smolen, K, Willems, F, Kollmann, T, Marchant, A. Transfer of maternal anti-microbial immunity to HIV-exposed uninfected newborns. Front Immunol. 2016; 7: 338.
[64]Slogrove, AL, Goetghebuer, T, Cotton, MF, Singer, J, Bettinger, JA. Pattern of infectious morbidity in HIV-exposed uninfected infants and children. Front Immunol. 2016; 7: 164.