1932

Abstract

Neonatal CD4+ and CD8+ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-091319-083608
2020-04-26
2024-10-05
Loading full text...

Full text loading...

/deliver/fulltext/immunol/38/1/annurev-immunol-091319-083608.html?itemId=/content/journals/10.1146/annurev-immunol-091319-083608&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Billingham RE, Brent L, Medawar PB 1953. Actively acquired tolerance of foreign cells. Nature 172:603–6
    [Google Scholar]
  2. 2. 
    Gammon G, Dunn K, Shastri N, Oki A, Wilbur S, Sercarz EE 1986. Neonatal T-cell tolerance to minimal immunogenic peptides is caused by clonal inactivation. Nature 319:413–15
    [Google Scholar]
  3. 3. 
    Forsthuber T, Yip HC, Lehmann PV 1996. Induction of TH1 and TH2 immunity in neonatal mice. Science 271:1728–30
    [Google Scholar]
  4. 4. 
    Singh RR, Hahn BH, Sercarz EE 1996. Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody versus T cell-mediated autoimmunity. J. Exp. Med. 183:1613–21
    [Google Scholar]
  5. 5. 
    Chen N, Field EH. 1995. Enhanced type 2 and diminished type 1 cytokines in neonatal tolerance. Transplantation 59:933–41
    [Google Scholar]
  6. 6. 
    Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG 1999. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 353:196–200
    [Google Scholar]
  7. 7. 
    Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S 2007. The role of inflammation and infection in preterm birth. Semin. Reprod. Med. 25:21–39
    [Google Scholar]
  8. 8. 
    Mold JE, Venkatasubrahmanyam S, Burt TD, Michaelsson J, Rivera JM et al. 2010. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330:1695–99
    [Google Scholar]
  9. 9. 
    Smith NL, Patel RK, Reynaldi A, Grenier JK, Wang J et al. 2018. Developmental origin governs CD8+ T cell fate decisions during infection. Cell 174:117–30.e14
    [Google Scholar]
  10. 10. 
    Zens KD, Chen JK, Guyer RS, Wu FL, Cvetkovski F et al. 2017. Reduced generation of lung tissue-resident memory T cells during infancy. J. Exp. Med. 214:2915–32
    [Google Scholar]
  11. 11. 
    Wang G, Miyahara Y, Guo Z, Khattar M, Stepkowski SM, Chen W 2010. “Default” generation of neonatal regulatory T cells. J. Immunol. 185:71–78
    [Google Scholar]
  12. 12. 
    Gibbons D, Fleming P, Virasami A, Michel ML, Sebire NJ et al. 2014. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat. Med. 20:1206–10
    [Google Scholar]
  13. 13. 
    Wissink EM, Smith NL, Spektor R, Rudd BD, Grimson A 2015. MicroRNAs and their targets are differentially regulated in adult and neonatal mouse CD8+ T cells. Genetics 201:1017–30
    [Google Scholar]
  14. 14. 
    Yu HR, Hsu TY, Huang HC, Kuo HC, Li SC et al. 2016. Comparison of the functional microRNA expression in immune cell subsets of neonates and adults. Front. Immunol. 7:615
    [Google Scholar]
  15. 15. 
    Palin AC, Ramachandran V, Acharya S, Lewis DB 2013. Human neonatal naive CD4+ T cells have enhanced activation-dependent signaling regulated by the microRNA miR-181a. J. Immunol. 190:2682–91
    [Google Scholar]
  16. 16. 
    Hayakawa K, Hardy RR, Herzenberg LA, Herzenberg LA 1985. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J. Exp. Med. 161:1554–68
    [Google Scholar]
  17. 17. 
    Kantor AB, Stall AM, Adams S, Herzenberg LA, Herzenberg LA 1992. Differential development of progenitor activity for three B-cell lineages. PNAS 89:3320–24
    [Google Scholar]
  18. 18. 
    Havran WL, Allison JP. 1988. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335:443–45
    [Google Scholar]
  19. 19. 
    Ikuta K, Kina T, MacNeil I, Uchida N, Peault B et al. 1990. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62:863–74
    [Google Scholar]
  20. 20. 
    Herzenberg LA, Herzenberg LA. 1989. Toward a layered immune system. Cell 59:953–54
    [Google Scholar]
  21. 21. 
    Jotereau F, Heuze F, Salomon-Vie V, Gascan H 1987. Cell kinetics in the fetal mouse thymus: precursor cell input, proliferation, and emigration. J. Immunol 138:1026–30
    [Google Scholar]
  22. 22. 
    Douagi I, Andre I, Ferraz JC, Cumano A 2000. Characterization of T cell precursor activity in the murine fetal thymus: evidence for an input of T cell precursors between days 12 and 14 of gestation. Eur. J. Immunol. 30:2201–10
    [Google Scholar]
  23. 23. 
    Adkins B. 1991. Developmental regulation of the intrathymic T cell precursor population. J. Immunol. 146:1387–93
    [Google Scholar]
  24. 24. 
    Kim I, Saunders TL, Morrison SJ 2007. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130:470–83
    [Google Scholar]
  25. 25. 
    Wang J, Wissink EM, Watson NB, Smith NL, Grimson A, Rudd BD 2016. Fetal and adult progenitors give rise to unique populations of CD8+ T cells. Blood 128:3073–82
    [Google Scholar]
  26. 26. 
    Adkins B. 2003. Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally. J. Immunol. 171:5157–64
    [Google Scholar]
  27. 27. 
    Hebel K, Weinert S, Kuropka B, Knolle J, Kosak B et al. 2014. CD4+ T cells from human neonates and infants are poised spontaneously to run a nonclassical IL-4 program. J. Immunol. 192:5160–70
    [Google Scholar]
  28. 28. 
    Webster RB, Rodriguez Y, Klimecki WT, Vercelli D 2007. The human IL-13 locus in neonatal CD4+ T cells is refractory to the acquisition of a repressive chromatin architecture. J. Biol. Chem. 282:700–9
    [Google Scholar]
  29. 29. 
    Smith NL, Wissink E, Wang J, Pinello JF, Davenport MP et al. 2014. Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life. J. Immunol. 193:177–84
    [Google Scholar]
  30. 30. 
    Reynaldi A, Smith NL, Schlub TE, Venturi V, Rudd BD, Davenport MP 2016. Modeling the dynamics of neonatal CD8+ T-cell responses. Immunol. Cell Biol 94:838–48
    [Google Scholar]
  31. 31. 
    McCarron MJ, Reen DJ. 2010. Neonatal CD8+ T-cell differentiation is dependent on interleukin-12. Hum. Immunol. 71:1172–79
    [Google Scholar]
  32. 32. 
    Marchant A, Goetghebuer T, Ota MO, Wolfe I, Ceesay SJ et al. 1999. Newborns develop a Th1-type immune response to Mycobacteriumbovis bacillus Calmette-Guerin vaccination. J. Immunol. 163:2249–55
    [Google Scholar]
  33. 33. 
    Mascart F, Verscheure V, Malfroot A, Hainaut M, Pierard D et al. 2003. Bordetellapertussis infection in 2-month-old infants promotes type 1 T cell responses. J. Immunol. 170:1504–9
    [Google Scholar]
  34. 34. 
    Reibke R, Garbi N, Ganss R, Hammerling GJ, Arnold B, Oelert T 2006. CD8+ regulatory T cells generated by neonatal recognition of peripheral self-antigen. PNAS 103:15142–47
    [Google Scholar]
  35. 35. 
    Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D 2015. Immune tolerance: Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348:589–94
    [Google Scholar]
  36. 36. 
    Mold JE, Michaelsson J, Burt TD, Muench MO, Beckerman KP et al. 2008. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322:1562–65
    [Google Scholar]
  37. 37. 
    Reynaldi A, Smith NL, Schlub TE, Tabilas C, Venturi V et al. 2019. Fate mapping reveals the age structure of the peripheral T cell compartment. PNAS 116:3974–81
    [Google Scholar]
  38. 38. 
    Montecino-Rodriguez E, Leathers H, Dorshkind K 2006. Identification of a B-1 B cell-specified progenitor. Nat. Immunol. 7:293–301
    [Google Scholar]
  39. 39. 
    Berland R, Wortis HH. 2002. Origins and functions of B-1 cells with notes on the role of CD5. Annu. Rev. Immunol. 20:253–300
    [Google Scholar]
  40. 40. 
    Bogue M, Candeias S, Benoist C, Mathis D 1991. A special repertoire of alpha:beta T cells in neonatal mice. EMBO J 10:3647–54
    [Google Scholar]
  41. 41. 
    Hardy RR, Hayakawa K. 2015. Perspectives on fetal derived CD5+ B1 B cells. Eur. J. Immunol. 45:2978–84
    [Google Scholar]
  42. 42. 
    Li YS, Zhou Y, Tang L, Shinton SA, Hayakawa K, Hardy RR 2015. A developmental switch between fetal and adult B lymphopoiesis. Ann. N. Y. Acad. Sci. 1362:8–15
    [Google Scholar]
  43. 43. 
    Zhou Y, Li YS, Bandi SR, Tang L, Shinton SA et al. 2015. Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a. J. Exp. Med. 212:569–80
    [Google Scholar]
  44. 44. 
    Yuan J, Nguyen CK, Liu X, Kanellopoulou C, Muljo SA 2012. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335:1195–200
    [Google Scholar]
  45. 45. 
    Montecino-Rodriguez E, Dorshkind K. 2006. New perspectives in B-1 B cell development and function. Trends Immunol 27:428–33
    [Google Scholar]
  46. 46. 
    Bedoui S, Gebhardt T, Gasteiger G, Kastenmuller W 2016. Parallels and differences between innate and adaptive lymphocytes. Nat. Immunol. 17:490–94
    [Google Scholar]
  47. 47. 
    Wells AC, Daniels KA, Angelou CC, Fagerberg E, Burnside AS et al. 2017. Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells. eLife 6:e26398
    [Google Scholar]
  48. 48. 
    Thornton JE, Gregory RI. 2012. How does Lin28 let-7 control development and disease. ? Trends Cell Biol 22:474–82
    [Google Scholar]
  49. 49. 
    Zhu H, Shyh-Chang N, Segre AV, Shinoda G, Shah SP et al. 2011. The Lin28/let-7 axis regulates glucose metabolism. Cell 147:81–94
    [Google Scholar]
  50. 50. 
    Tabilas C, Wang J, Xiajoing L, Locasale JW, Smith NL, Rudd BD 2019. Cutting edge: Elevated glycolytic metabolism limits the formation of memory CD8+ T cells in early life. J. Immunol. 203:2571–76 https://doi.org/10.4049/jimmunol.1900426
    [Crossref] [Google Scholar]
  51. 51. 
    Bronevetsky Y, Burt TD, McCune JM 2016. Lin28b regulates fetal regulatory T cell differentiation through modulation of TGF-β signaling. J. Immunol. 197:4344–50
    [Google Scholar]
  52. 52. 
    Li QJ, Chau J, Ebert PJ, Sylvester G, Min H et al. 2007. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129:147–61
    [Google Scholar]
  53. 53. 
    Li G, Yu M, Lee WW, Tsang M, Krishnan E et al. 2012. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18:1518–24
    [Google Scholar]
  54. 54. 
    Schietinger A, Delrow JJ, Basom RS, Blattman JN, Greenberg PD 2012. Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state. Science 335:723–27
    [Google Scholar]
  55. 55. 
    Cabaniols JP, Fazilleau N, Casrouge A, Kourilsky P, Kanellopoulos JM 2001. Most α/β T cell receptor diversity is due to terminal deoxynucleotidyl transferase. J. Exp. Med. 194:1385–90
    [Google Scholar]
  56. 56. 
    Gilfillan S, Dierich A, Lemeur M, Benoist C, Mathis D 1993. Mice lacking TdT: mature animals with an immature lymphocyte repertoire. Science 261:1175–78
    [Google Scholar]
  57. 57. 
    Bogue M, Gilfillan S, Benoist C, Mathis D 1992. Regulation of N-region diversity in antigen receptors through thymocyte differentiation and thymus ontogeny. PNAS 89:11011–15
    [Google Scholar]
  58. 58. 
    Feeney AJ. 1991. Junctional sequences of fetal T cell receptor beta chains have few N regions. J. Exp. Med. 174:115–24
    [Google Scholar]
  59. 59. 
    Schelonka RL, Raaphorst FM, Infante D, Kraig E, Teale JM, Infante AJ 1998. T cell receptor repertoire diversity and clonal expansion in human neonates. Pediatr. Res. 43:396–402
    [Google Scholar]
  60. 60. 
    Dong M, Artusa P, Kelly SA, Fournier M, Baldwin TA et al. 2017. Alterations in the thymic selection threshold skew the self-reactivity of the TCR repertoire in neonates. J. Immunol. 199:965–73
    [Google Scholar]
  61. 61. 
    Mandl JN, Monteiro JP, Vrisekoop N, Germain RN 2013. T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity 38:263–74
    [Google Scholar]
  62. 62. 
    White JT, Cross EW, Burchill MA, Danhorn T, McCarter MD et al. 2016. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat. Commun. 7:11291
    [Google Scholar]
  63. 63. 
    Cho JH, Kim HO, Surh CD, Sprent J 2010. T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32:214–26
    [Google Scholar]
  64. 64. 
    Fulton RB, Hamilton SE, Xing Y, Best JA, Goldrath AW et al. 2015. The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8+ T cells to respond to foreign antigens. Nat. Immunol. 16:107–17
    [Google Scholar]
  65. 65. 
    Baumgarth N. 2011. The double life of a B-1 cell: Self-reactivity selects for protective effector functions. Nat. Rev. Immunol. 11:34–46
    [Google Scholar]
  66. 66. 
    Carey AJ, Hope JL, Mueller YM, Fike AJ, Kumova OK et al. 2017. Public clonotypes and convergent recombination characterize the naive CD8+ T-cell receptor repertoire of extremely preterm neonates. Front. Immunol. 8:1859
    [Google Scholar]
  67. 67. 
    Venturi V, Nzingha K, Amos TG, Charles WC, Dekhtiarenko I et al. 2016. The neonatal CD8+ T cell repertoire rapidly diversifies during persistent viral infection. J. Immunol. 196:1604–16
    [Google Scholar]
  68. 68. 
    Rudd BD, Venturi V, Smith NL, Nzingha K, Goldberg EL et al. 2013. Acute neonatal infections ‘lock-in’ a suboptimal CD8+ T cell repertoire with impaired recall responses. PLOS Pathog 9:e1003572
    [Google Scholar]
  69. 69. 
    Rudd BD, Venturi V, Davenport MP, Nikolich-Zugich J 2011. Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J. Immunol. 186:2056–64
    [Google Scholar]
  70. 70. 
    Ruckwardt TJ, Malloy AM, Gostick E, Price DA, Dash P et al. 2011. Neonatal CD8 T-cell hierarchy is distinct from adults and is influenced by intrinsic T cell properties in respiratory syncytial virus infected mice. PLOS Pathog 7:e1002377
    [Google Scholar]
  71. 71. 
    Gilfillan S, Bachmann M, Trembleau S, Adorini L, Kalinke U et al. 1995. Efficient immune responses in mice lacking N-region diversity. Eur. J. Immunol. 25:3115–22
    [Google Scholar]
  72. 72. 
    Gavin MA, Bevan MJ. 1995. Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire. Immunity 3:793–800
    [Google Scholar]
  73. 73. 
    Conde C, Weller S, Gilfillan S, Marcellin L, Martin T, Pasquali JL 1998. Terminal deoxynucleotidyl transferase deficiency reduces the incidence of autoimmune nephritis in (New Zealand Black × New Zealand White)F1 mice. J. Immunol. 161:7023–30
    [Google Scholar]
  74. 74. 
    Feeney AJ, Lawson BR, Kono DH, Theofilopoulos AN 2001. Terminal deoxynucleotidyl transferase deficiency decreases autoimmune disease in MRL-Faslpr mice. J. Immunol. 167:3486–93
    [Google Scholar]
  75. 75. 
    Robey IF, Peterson M, Horwitz MS, Kono DH, Stratmann T et al. 2004. Terminal deoxynucleotidyltransferase deficiency decreases autoimmune disease in diabetes-prone nonobese diabetic mice and lupus-prone MRL-Faslpr mice. J. Immunol. 172:4624–29
    [Google Scholar]
  76. 76. 
    Houston EG Jr, Fink PJ. 2009. MHC drives TCR repertoire shaping, but not maturation, in recent thymic emigrants. J. Immunol. 183:7244–49
    [Google Scholar]
  77. 77. 
    Matsutani T, Ohmori T, Ogata M, Soga H, Kasahara S et al. 2007. Comparison of CDR3 length among thymocyte subpopulations: impacts of MHC and BV segment on the CDR3 shortening. Mol. Immunol. 44:2378–87
    [Google Scholar]
  78. 78. 
    He Q, Morillon YM 2nd, Spidale NA, Kroger CJ, Liu B et al. 2013. Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner. J. Immunol. 191:5858–66
    [Google Scholar]
  79. 79. 
    Gilfillan S, Benoist C, Mathis D 1995. Mice lacking terminal deoxynucleotidyl transferase: adult mice with a fetal antigen receptor repertoire. Immunol. Rev. 148:201–19
    [Google Scholar]
  80. 80. 
    Halkias J, Rackaityte E, Hillman SL, Aran D, Mendoza VF et al. 2019. CD161 contributes to prenatal immune suppression of IFNγ-producing PLZF+ T cells. J. Clin. Investig. 130:3562–77
    [Google Scholar]
  81. 81. 
    McCarron M, Reen DJ. 2009. Activated human neonatal CD8+ T cells are subject to immunomodulation by direct TLR2 or TLR5 stimulation. J. Immunol. 182:55–62
    [Google Scholar]
  82. 82. 
    Galindo-Albarran AO, Lopez-Portales OH, Gutierrez-Reyna DY, Rodriguez-Jorge O, Sanchez-Villanueva JA et al. 2016. CD8+ T cells from human neonates are biased toward an innate immune response. Cell Rep 17:2151–60
    [Google Scholar]
  83. 83. 
    Komai-Koma M, Jones L, Ogg GS, Xu D, Liew FY 2004. TLR2 is expressed on activated T cells as a costimulatory receptor. PNAS 101:3029–34
    [Google Scholar]
  84. 84. 
    Sinnott BD, Park B, Boer MC, Lewinsohn DA, Lancioni CL 2016. Direct TLR-2 costimulation unmasks the proinflammatory potential of neonatal CD4+ T cells. J. Immunol. 197:68–77
    [Google Scholar]
  85. 85. 
    Siefker DT, Adkins B. 2016. Rapid CD8+ function is critical for protection of neonatal mice from an extracellular bacterial enteropathogen. Front. Pediatr. 4:141
    [Google Scholar]
  86. 86. 
    van den Broek T, Delemarre EM, Janssen WJ, Nievelstein RA, Broen JC et al. 2016. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells. J. Clin. Investig. 126:1126–36
    [Google Scholar]
  87. 87. 
    Pekalski ML, Garcia AR, Ferreira RC, Rainbow DB, Smyth DJ et al. 2017. Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. JCI Insight 2:93739
    [Google Scholar]
  88. 88. 
    Das A, Rouault-Pierre K, Kamdar S, Gomez-Tourino I, Wood K et al. 2017. Adaptive from innate: Human IFN-γ+CD4+ T cells can arise directly from CXCL8-producing recent thymic emigrants in babies and adults. J. Immunol. 199:1696–705
    [Google Scholar]
  89. 89. 
    Cerutti A, Cols M, Puga I 2013. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat. Rev. Immunol. 13:118–32
    [Google Scholar]
  90. 90. 
    Scheible KM, Emo J, Laniewski N, Baran AM, Peterson DR et al. 2018. T cell developmental arrest in former premature infants increases risk of respiratory morbidity later in infancy. JCI Insight 3:96724
    [Google Scholar]
  91. 91. 
    Matzinger P. 1994. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12:991–1045
    [Google Scholar]
  92. 92. 
    Janeway CA Jr 1989. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54:Part 11–13
    [Google Scholar]
  93. 93. 
    Hunter MC, Teijeira A, Halin C 2016. T cell trafficking through lymphatic vessels. Front. Immunol. 7:613
    [Google Scholar]
  94. 94. 
    Masopust D, Schenkel JM. 2013. The integration of T cell migration, differentiation and function. Nat. Rev. Immunol. 13:309–20
    [Google Scholar]
  95. 95. 
    Mackay CR, Marston WL, Dudler L 1990. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171:801–17
    [Google Scholar]
  96. 96. 
    Mackay CR, Kimpton WG, Brandon MR, Cahill RN 1988. Lymphocyte subsets show marked differences in their distribution between blood and the afferent and efferent lymph of peripheral lymph nodes. J. Exp. Med. 167:1755–65
    [Google Scholar]
  97. 97. 
    Scharschmidt TC, Vasquez KS, Truong HA, Gearty SV, Pauli ML et al. 2015. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43:1011–21
    [Google Scholar]
  98. 98. 
    Alferink J, Tafuri A, Vestweber D, Hallmann R, Hammerling GJ, Arnold B 1998. Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking. Science 282:1338–41
    [Google Scholar]
  99. 99. 
    Staton TL, Habtezion A, Winslow MM, Sato T, Love PE, Butcher EC 2006. CD8+ recent thymic emigrants home to and efficiently repopulate the small intestine epithelium. Nat. Immunol. 7:482–88
    [Google Scholar]
  100. 100. 
    Crespo M, Martinez DG, Cerissi A, Rivera-Reyes B, Bernstein HB et al. 2012. Neonatal T-cell maturation and homing receptor responses to Toll-like receptor ligands differ from those of adult naive T cells: relationship to prematurity. Pediatr. Res. 71:136–43
    [Google Scholar]
  101. 101. 
    Shi J, Wei PK. 2016. Interleukin-8: a potent promoter of angiogenesis in gastric cancer. Oncol. Lett. 11:1043–50
    [Google Scholar]
  102. 102. 
    Thome JJ, Bickham KL, Ohmura Y, Kubota M, Matsuoka N et al. 2016. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat. Med. 22:72–77
    [Google Scholar]
  103. 103. 
    Fernandez MA, Puttur FK, Wang YM, Howden W, Alexander SI, Jones CA 2008. T regulatory cells contribute to the attenuated primary CD8+ and CD4+ T cell responses to herpes simplex virus type 2 in neonatal mice. J. Immunol. 180:1556–64
    [Google Scholar]
  104. 104. 
    Connors TJ, Baird JS, Yopes MC, Zens KD, Pethe K et al. 2018. Developmental regulation of effector and resident memory T cell generation during pediatric viral respiratory tract infection. J. Immunol. 201:432–39
    [Google Scholar]
  105. 105. 
    Chang J, Braciale TJ. 2002. Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and peripheral CD8+ T-cell memory in the respiratory tract. Nat. Med. 8:54–60
    [Google Scholar]
  106. 106. 
    Huygens A, Lecomte S, Tackoen M, Olislagers V, Delmarcelle Y et al. 2015. Functional exhaustion limits CD4+ and CD8+ T-cell responses to congenital cytomegalovirus infection. J. Infect. Dis. 212:484–94
    [Google Scholar]
  107. 107. 
    Kollmann TR, Reikie B, Blimkie D, Way SS, Hajjar AM et al. 2007. Induction of protective immunity to Listeriamonocytogenes in neonates. J. Immunol. 178:3695–701
    [Google Scholar]
  108. 108. 
    Fadel SA, Cowell LG, Cao S, Ozaki DA, Kepler TB et al. 2006. Neonate-primed CD8+ memory cells rival adult-primed memory cells in antigen-driven expansion and anti-viral protection. Int. Immunol. 18:249–57
    [Google Scholar]
  109. 109. 
    Sarzotti M, Robbins DS, Hoffman PM 1996. Induction of protective CTL responses in newborn mice by a murine retrovirus. Science 271:1726–28
    [Google Scholar]
  110. 110. 
    Hiwarkar P, Hubank M, Qasim W, Chiesa R, Gilmour KC et al. 2017. Cord blood transplantation recapitulates fetal ontogeny with a distinct molecular signature that supports CD4+ T-cell reconstitution. Blood Adv 1:2206–16
    [Google Scholar]
  111. 111. 
    Hiwarkar P, Qasim W, Ricciardelli I, Gilmour K, Quezada S et al. 2015. Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells. Blood 126:2882–91
    [Google Scholar]
  112. 112. 
    Lee YS, Kim TS, Kim DK 2011. T lymphocytes derived from human cord blood provide effective antitumor immunotherapy against a human tumor. BMC Cancer 11:225
    [Google Scholar]
  113. 113. 
    St. John LS, Wan L, He H, Garber HR, Clise-Dwyer K et al. 2016. PR1-specific cytotoxic T lymphocytes are relatively frequent in umbilical cord blood and can be effectively expanded to target myeloid leukemia. Cytotherapy 18:995–1001
    [Google Scholar]
  114. 114. 
    Hanley PJ, Cruz CR, Savoldo B, Leen AM, Stanojevic M et al. 2009. Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood 114:1958–67
    [Google Scholar]
  115. 115. 
    Schonland SO, Zimmer JK, Lopez-Benitez CM, Widmann T, Ramin KD et al. 2003. Homeostatic control of T-cell generation in neonates. Blood 102:1428–34
    [Google Scholar]
  116. 116. 
    Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G et al. 2013. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 121:573–84
    [Google Scholar]
  117. 117. 
    Schaub B, Liu J, Hoppler S, Schleich I, Huehn J et al. 2009. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J. Allergy Clin. Immunol. 123:774–82.e5
    [Google Scholar]
  118. 118. 
    Risnes KR, Belanger K, Murk W, Bracken MB 2011. Antibiotic exposure by 6 months and asthma and allergy at 6 years: findings in a cohort of 1,401 US children. Am. J. Epidemiol. 173:310–18
    [Google Scholar]
  119. 119. 
    Shaw SY, Blanchard JF, Bernstein CN 2010. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am. J. Gastroenterol. 105:2687–92
    [Google Scholar]
  120. 120. 
    Kronman MP, Zaoutis TE, Haynes K, Feng R, Coffin SE 2012. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics 130:e794–803
    [Google Scholar]
/content/journals/10.1146/annurev-immunol-091319-083608
Loading
/content/journals/10.1146/annurev-immunol-091319-083608
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error