Advertisement

Seminars in Immunopathology

, Volume 39, Issue 6, pp 577–583 | Cite as

Survival of the fetus: fetal B and T cell receptor repertoire development

  • Erez Rechavi
  • Raz SomechEmail author
Review

Abstract

A mature and diverse T and B cell receptor repertoire is a prerequisite for immunocompetence. In light of its increased susceptibility to infection, the human fetus has long been considered deficient in this regard. However, data accumulated since the 1990s and in earnest in the past couple of years paints a more complicated picture. As we describe in this review, mechanisms responsible for generating a diverse receptor repertoire, such as somatic recombination, class switch recombination, and somatic hypermutation, are all operational to surprising extents in the growing fetus. The composition of the fetal repertoire differs from that of adults, with preferential usage of certain variable (V), diversity (D), and joining (J) gene segments and a shorter complementarity determining (CDR3) region, primarily due to decreased terminal deoxynucleotidyl transferase (TdT) expression. Both T and B cell receptor repertoires are extremely diverse by the end of the second trimester, and in the case of T cells, are capable of responding to an invading pathogen with in utero clonal expansion. Thus, it would appear as though the T and B cell receptor repertoires are not a hindrance towards immunocompetence of the newborn. Our improved understanding of fetal receptor repertoire development is already bearing fruit in the early diagnosis of primary immunodeficiencies (PID) and may help clarify the pathogenesis of congenital infections, recurrent abortions, and autoimmune disorders in the near future.

Keywords

Fetal immunity T cell receptor B cell receptor Receptor repertoire Development Next-generation sequencing Immunocompetence 

Notes

Acknowledgments

Raz Somech is supported by the Jeffrey Modell Foundation (JMF). This review and some of the work were performed in partial fulfillment of the requirements of the PhD of Erez Rechavi at the Sackler School of Medicine (Tel Aviv University).

References

  1. 1.
    Marchant A, Kollmann TR (2015) Understanding the ontogeny of the immune system to promote immune-mediated health for life. Front Immunol 6(77):1–3Google Scholar
  2. 2.
    Niewiesk S (2014) Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies. Front Immunol 5(446):1–15Google Scholar
  3. 3.
    Leveque L, Khosrotehrani K (2014) Feto-maternal allo-immunity, regulatory T cells and predisposition to auto-immunity. Does it all start in utero? Chimerism 5(2):59–62CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Taub JW, Ge Y (2004) The prenatal origin of childhood acute lymphoblastic leukemia. Leuk Lymphoma 45(1):19–25CrossRefPubMedGoogle Scholar
  5. 5.
    Tonegawa S, Steinberg C, Bernardinj A (1974) Evidence for somatic generation of antibody diversity. Proc Natl Acad Sci 71(10):4027–4031CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zemlin M, Schelonka RL, Bauer K, Schroeder HW (2002) Regulation and chance in the ontogeny of B and T cell. Immunol Res 26:265–278CrossRefPubMedGoogle Scholar
  7. 7.
    Douek DC et al (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396(6712):690–695CrossRefPubMedGoogle Scholar
  8. 8.
    Langerak AW et al (2004) Unraveling the consecutive recombination events in the human IGK locus. J Immunol 173:3878–3888CrossRefPubMedGoogle Scholar
  9. 9.
    Kwan A, Puck JM (2015) History and current status of newborn screening for severe combined immunodeficiency. Semin Perinatol 39(3):194–205CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hochberg EP et al (2001) Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. Blood 98(4):1116–1121CrossRefPubMedGoogle Scholar
  11. 11.
    Amariglio N, Lev A, Simon AJ et al (2010) Molecular assessment of thymus capabilities in the evaluation of T-cell immunodeficiency. Pediatr Res 67(2):211–216CrossRefPubMedGoogle Scholar
  12. 12.
    Schroeder HW, Wang J (1990) Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc Natl Acad Sci 87:6146–6150CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Raaphorst FM et al (1994) Usage of TCRAV and TCRBV gene families in human fetal and adult TCR rearrangements. Immunogenetics 39(5):343–350CrossRefPubMedGoogle Scholar
  14. 14.
    Rechavi E, Lev A, Lee YN et al (2015) Timely and spatially regulated maturation of B and T cell repertoire during human fetal development. Sci Transl Med 7(276):1–12CrossRefGoogle Scholar
  15. 15.
    Nickerson KG, Berman J, Glickman E, Chess L, Alt F (1989) Early human IgH gene assembly in Epstein-Barr virus-transformed fetal B cell lines. J Exp Med 169:1391–1403CrossRefPubMedGoogle Scholar
  16. 16.
    Souto-Carneiro MM, Sims GP, Girschik H, Lee J, Lipsky PE (2005) Developmental changes in the human heavy chain CDR3. J Immunol 175(11):7425–7436CrossRefPubMedGoogle Scholar
  17. 17.
    Zemlin M et al (2001) The diversity of rearranged immunoglobulin heavy chain variable region genes in peripheral blood B cells of preterm infants is restricted by short third complementarity-determining regions but not by limited gene segment usage. Blood 97(5):1511–1513CrossRefPubMedGoogle Scholar
  18. 18.
    Rother MB et al (2016) Decreased IL7Rα and TdT expression underlie the skewed immunoglobulin repertoire of human B-cell precursors from fetal origin. Sci Rep 6:33924. doi: 10.1038/srep33924 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pascual V, Verkruyse L, Casey ML, Capra JD (1993) Analysis of IgH chain gene segment utilization in human fetal liver. J Immunol 151:4164–4172PubMedGoogle Scholar
  20. 20.
    Schroeder HW, Zhang L, Philips JB (2001) Slow, programmed maturation of the immunoglobulin HCDR3 repertoire during the third trimester of fetal life. Blood 98(9):2745–2751CrossRefPubMedGoogle Scholar
  21. 21.
    Zemlin M et al (2007) The postnatal maturation of the immunoglobulin heavy chain IgG repertoire in human preterm neonates is slower than in term neonates. J Immunol 178(2):1180–1188CrossRefPubMedGoogle Scholar
  22. 22.
    Griffiths PD, Stagno S, Pass RF, Smith RJ, Alford CA Jr (1982) Congenital cytomegalovirus infection: diagnostic and prognostic significance of the detection of specific immunoglobulin M antibodies in cord serum. Pediatrics 69(5):544–549PubMedGoogle Scholar
  23. 23.
    George JF, Schroeder HW (1992) Developmental regulation of D beta reading frame and junctional diversity in T cell receptor-beta transcripts from human thymus. J Immunol 148(4):1230–1239PubMedGoogle Scholar
  24. 24.
    Raaphorst FM, Kaijzel EL, van Tol MJ, Vossen JM, van den Elsen PJ (1994) Non-random employment of V beta 6 and J beta gene elements and conserved amino acid usage profiles in CDR3 regions of human fetal and adult TCR beta chain rearrangements. Int Immunol 6(1):1–9CrossRefPubMedGoogle Scholar
  25. 25.
    Prabakaran P et al (2012) Expressed antibody repertoires in human cord blood cells: 454 sequencing and IMGT/HighV-QUEST analysis of germline gene usage, junctional diversity, and somatic mutations. Immunogenetics 64(5):337–350CrossRefPubMedGoogle Scholar
  26. 26.
    Gavin MA, Bevan MJ (1995) Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire. Immunity 3(6):793–800CrossRefPubMedGoogle Scholar
  27. 27.
    Miles DJC et al (2007) Cytomegalovirus infection in Gambian infants leads to profound CD8 T-cell differentiation. J Virol 81(11):5766–5776CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Marchant A et al (2003) Mature CD8+ T lymphocyte response to viral infection during fetal life. J Clin Invest 111(11):1747–1755CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Huygens A et al. (2015) Functional exhaustion limits CD4+ and CD8+ T-cell responses to congenital cytomegalovirus infection J Infect Dis 212(3):484–494.Google Scholar
  30. 30.
    Babik JM, Cohan D, Monto A, Hartigan-O’Connor DJ, McCune JM (2011) The human fetal immune response to hepatitis C virus exposure in utero. J Infect Dis 203(2):196–206CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Forestier F, Daffos F, Catherine N, Renard M, Andreux JP (1991) Developmental hematopoiesis in normal human fetal blood. Blood 77(11):2360–2363PubMedGoogle Scholar
  32. 32.
    Barbaro M et al (2017) Newborn screening for severe primary immunodeficiency diseases in Sweden—a 2-year pilot TREC and KREC screening study. J Clin Immunol 37(1):51–60CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, “Edmond and Lily Safra” Children’s Hospital, Sheba Medical Center, Tel Hashomer, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael

Personalised recommendations