Abstract
We are just beginning to understand the diversity of the peripheral T cell compartment, which arises from the specialization of different T cell subsets and the plasticity of individual naive T cells to adopt different fates. Although the progeny of a single T cell can differentiate into many phenotypes following infection, individual T cells are biased towards particular phenotypes. These biases are typically ascribed to random factors that occur during and after antigenic stimulation. However, the T cell compartment does not remain static with age, and shifting immune challenges during ontogeny give rise to T cells with distinct functional properties. Here, we argue that the developmental history of naive T cells creates a ‘hidden layer’ of diversity that persists into adulthood. Insight into this diversity can provide a new perspective on immunity and immunotherapy across the lifespan.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
van Hoeven, V. et al. Dynamics of recent thymic emigrants in young adult mice. Front. Immunol. 8, 933 (2017).
den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288–297 (2012).
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Mackay, C. R. Homing of naive, memory and effector lymphocytes. Curr. Opin. Immunol. 5, 423–427 (1993).
Jameson, S. C. & Masopust, D. Understanding subset diversity in T cell memory. Immunity 48, 214–226 (2018).
Omilusik, K. D. & Goldrath, A. W. Remembering to remember: T cell memory maintenance and plasticity. Curr. Opin. Immunol. 58, 89–97 (2019).
Kumar, B. V., Connors, T. J. & Farber, D. L. Human T cell development, localization, and function throughout life. Immunity 48, 202–213 (2018).
Marshall, H. D. et al. Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4+ cell properties during viral infection. Immunity 35, 633–646 (2011).
Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).
van den Broek, T., Borghans, J. A. M. & van Wijk, F. The full spectrum of human naive T cells. Nat. Rev. Immunol. 18, 363–373 (2018).
Stemberger, C. et al. A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity 27, 985–997 (2007).
Plumlee, C. R., Sheridan, B. S., Cicek, B. B. & Lefrancois, L. Environmental cues dictate the fate of individual CD8+ T cells responding to infection. Immunity 39, 347–356 (2013).
Gerlach, C. et al. Heterogeneous differentiation patterns of individual CD8+ T cells. Science 340, 635–639 (2013).
Joshi, N. S. et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007).
van Faassen, H. et al. Reducing the stimulation of CD8+ T cells during infection with intracellular bacteria promotes differentiation primarily into a central (CD62LhighCD44high) subset. J. Immunol. 174, 5341–5350 (2005).
Masson, F., Mount, A. M., Wilson, N. S. & Belz, G. T. Dendritic cells: driving the differentiation programme of T cells in viral infections. Immunol. Cell Biol. 86, 333–342 (2008).
Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).
Hendricks, D. W. & Fink, P. J. Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage. Blood 117, 1239–1249 (2011).
Makaroff, L. E., Hendricks, D. W., Niec, R. E. & Fink, P. J. Postthymic maturation influences the CD8 T cell response to antigen. Proc. Natl Acad. Sci. USA 106, 4799–4804 (2009).
Mold, J. E. et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695–1699 (2010).
Reynaldi, A. et al. Modeling the dynamics of neonatal CD8+ T-cell responses. Immunol. Cell Biol. 94, 838–848 (2016).
Tabilas, C. et al. Cutting edge: elevated glycolytic metabolism limits the formation of memory CD8+ T cells in early life. J. Immunol. 203, 2571–2576 (2019).
Wang, J. et al. Fetal and adult progenitors give rise to unique populations of CD8+ T cells. Blood 128, 3073–3082 (2016).
Smith, N. L. et al. Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life. J. Immunol. 193, 177–184 (2014).
Zens, K. D. et al. Reduced generation of lung tissue-resident memory T cells during infancy. J. Exp. Med. 214, 2915–2932 (2017).
Reynaldi, A. et al. Fate mapping reveals the age structure of the peripheral T cell compartment. Proc. Natl Acad. Sci. USA 116, 3974–3981 (2019).
Smith, N. L. et al. Developmental origin governs CD8(+) T cell fate decisions during infection. Cell 174, 117–130.e114 (2018).
Yang, S., Fujikado, N., Kolodin, D., Benoist, C. & Mathis, D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348, 589–594 (2015).
Pogorelyy, M. V. et al. Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires. PLoS Comput. Biol. 13, e1005572 (2017).
Zhang, B. et al. Glimpse of natural selection of long-lived T-cell clones in healthy life. Proc. Natl Acad. Sci. USA 113, 9858–9863 (2016).
Mold, J. E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562–1565 (2008).
Burt, T. D. Fetal regulatory T cells and peripheral immune tolerance in utero: implications for development and disease. Am. J. Reprod. Immunol. 69, 346–358 (2013).
Mold, J. E. & McCune, J. M. Immunological tolerance during fetal development: from mouse to man. Adv. Immunol. 115, 73–111 (2012).
Schonland, S. O. et al. Homeostatic control of T-cell generation in neonates. Blood 102, 1428–1434 (2003).
Le Campion, A. et al. Naive T cells proliferate strongly in neonatal mice in response to self-peptide/self-MHC complexes. Proc. Natl Acad. Sci. USA 99, 4538–4543 (2002).
Rudd, B. D. et al. Acute neonatal infections ‘lock-in’ a suboptimal CD8+ T cell repertoire with impaired recall responses. PLoS Pathog. 9, e1003572 (2013).
Rudd, B. D., Venturi, V., Davenport, M. P. & Nikolich-Zugich, J. Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J. Immunol. 186, 2056–2064 (2011).
Carey, A. J. et al. Public clonotypes and convergent recombination characterize the naive CD8+ T-cell receptor repertoire of extremely preterm neonates. Front. Immunol. 8, 1859 (2017).
Schelonka, R. L. et al. T cell receptor repertoire diversity and clonal expansion in human neonates. Pediatr. Res. 43, 396–402 (1998).
D’Arena, G. et al. Flow cytometric characterization of human umbilical cord blood lymphocytes: immunophenotypic features. Haematologica 83, 197–203 (1998).
Nikolich-Zugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol. 19, 10–19 (2018).
Goronzy, J. J. & Weyand, C. M. Mechanisms underlying T cell ageing. Nat. Rev. Immunol. 19, 573–583 (2019).
Thome, J. J. et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016).
Nikolich-Zugich, J., Slifka, M. K. & Messaoudi, I. The many important facets of T-cell repertoire diversity. Nat. Rev. Immunol. 4, 123–132 (2004).
Jotereau, F., Heuze, F., Salomon-Vie, V. & Gascan, H. Cell kinetics in the fetal mouse thymus: precursor cell input, proliferation, and emigration. J. Immunol. 138, 1026–1030 (1987).
Tavian, M. & Peault, B. The changing cellular environments of hematopoiesis in human development in utero. Exp. Hematol. 33, 1062–1069 (2005).
Herzenberg, L. A. & Herzenberg, L. A. Toward a layered immune system. Cell 59, 953–954 (1989).
Adkins, B. Developmental regulation of the intrathymic T cell precursor population. J. Immunol. 146, 1387–1393 (1991).
Ng, M. S. F., Roth, T. L., Mendoza, V. F., Marson, A. & Burt, T. D. Helios enhances the preferential differentiation of human fetal CD4(+) naive T cells into regulatory T cells. Sci. Immunol. 4, eaav5947 (2019).
Rudd, B. D. Neonatal T cells: a reinterpretation. Annu. Rev. Immunol. 38, 229–247 (2020).
Connors, T. J. et al. Developmental regulation of effector and resident memory T cell generation during pediatric viral respiratory tract infection. J. Immunol. 201, 432–439 (2018).
Siefker, D. T. & Adkins, B. Rapid CD8+ function is critical for protection of neonatal mice from an extracellular bacterial enteropathogen. Front. Pediatr. 4, 141 (2016).
Bogue, M., Candeias, S., Benoist, C. & Mathis, D. A special repertoire of alpha:beta T cells in neonatal mice. EMBO J. 10, 3647–3654 (1991).
Feeney, A. J. Junctional sequences of fetal T cell receptor beta chains have few N regions. J. Exp. Med. 174, 115–124 (1991).
Venturi, V. et al. The neonatal CD8+ T cell repertoire rapidly diversifies during persistent viral infection. J. Immunol. 196, 1604–1616 (2016).
Carey, A. J. et al. Rapid evolution of the CD8+ TCR repertoire in neonatal mice. J. Immunol. 196, 2602–2613 (2016).
Rechavi, E. & Somech, R. Survival of the fetus: fetal B and T cell receptor repertoire development. Semin. Immunopathol. 39, 577–583 (2017).
Gavin, M. A. & Bevan, M. J. Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire. Immunity 3, 793–800 (1995).
Kedzierska, K. et al. Terminal deoxynucleotidyltransferase is required for the establishment of private virus-specific CD8+ TCR repertoires and facilitates optimal CTL responses. J. Immunol. 181, 2556–2562 (2008).
Fink, P. J. The biology of recent thymic emigrants. Annu. Rev. Immunol. 31, 31–50 (2013).
Friesen, T. J., Ji, Q. & Fink, P. J. Recent thymic emigrants are tolerized in the absence of inflammation. J. Exp. Med. 213, 913–920 (2016).
He, Q. et al. Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner. J. Immunol. 191, 5858–5866 (2013).
Das, A. et al. 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, 1696–1705 (2017).
Akue, A. D., Lee, J. Y. & Jameson, S. C. Derivation and maintenance of virtual memory CD8 T cells. J. Immunol. 188, 2516–2523 (2012).
McCarron, M. & Reen, D. J. Activated human neonatal CD8+ T cells are subject to immunomodulation by direct TLR2 or TLR5 stimulation. J. Immunol. 182, 55–62 (2009).
Komai-Koma, M., Jones, L., Ogg, G. S., Xu, D. & Liew, F. Y. TLR2 is expressed on activated T cells as a costimulatory receptor. Proc. Natl Acad. Sci. USA 101, 3029–3034 (2004).
Sinnott, B. D., Park, B., Boer, M. C., Lewinsohn, D. A. & Lancioni, C. L. Direct TLR-2 costimulation unmasks the proinflammatory potential of neonatal CD4+ T cells. J. Immunol. 197, 68–77 (2016).
van den Broek, T. et al. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells. J. Clin. Invest. 126, 1126–1136 (2016).
Pekalski, M. L. et al. Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. JCI Insight 2, e93739 (2017).
Fulton, R. B. et al. The TCR’s sensitivity to self peptide-MHC dictates the ability of naive CD8+ T cells to respond to foreign antigens. Nat. Immunol. 16, 107–117 (2015).
White, J. T., Cross, E. W. & Kedl, R. M. Antigen-inexperienced memory CD8+ T cells: where they come from and why we need them. Nat. Rev. Immunol. 17, 391–400 (2017).
Lee, J. Y., Hamilton, S. E., Akue, A. D., Hogquist, K. A. & Jameson, S. C. Virtual memory CD8 T cells display unique functional properties. Proc. Natl Acad. Sci. USA 110, 13498–13503 (2013).
Haluszczak, C. et al. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J. Exp. Med. 206, 435–448 (2009).
Min, B. et al. Neonates support lymphopenia-induced proliferation. Immunity 18, 131–140 (2003).
Schuler, T., Hammerling, G. J. & Arnold, B. Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells. J. Immunol. 172, 15–19 (2004).
Jameson, S. C., Lee, Y. J. & Hogquist, K. A. Innate memory T cells. Adv. Immunol. 126, 173–213 (2015).
Goldrath, A. W., Bogatzki, L. Y. & Bevan, M. J. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557–564 (2000).
Mold, J. E. et al. Cell generation dynamics underlying naive T-cell homeostasis in adult humans. PLoS Biol. 17, e3000383 (2019).
Miller, R. A. The aging immune system: primer and prospectus. Science 273, 70–74 (1996).
Adkins, B., Guevara, P. & Rose, S. Thymic and extrathymic contributions to T helper cell function in murine neonates. Haematol. Rep. 2, 9–13 (2006).
White, J. T. et al. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat. Commun. 7, 11291 (2016).
Adkins, B. Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally. J. Immunol. 171, 5157–5164 (2003).
Adkins, B., Williamson, T., Guevara, P. & Bu, Y. Murine neonatal lymphocytes show rapid early cell cycle entry and cell division. J. Immunol. 170, 4548–4556 (2003).
Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).
Liston, A., Carr, E. J. & Linterman, M. A. Shaping variation in the human immune system. Trends Immunol. 37, 637–646 (2016).
Carr, E. J. et al. The cellular composition of the human immune system is shaped by age and cohabitation. Nat. Immunol. 17, 461–468 (2016).
Frisancho, A. R. Developmental functional adaptation to high altitude: review. Am. J. Hum. Biol. 25, 151–168 (2013).
Olin, A. et al. Stereotypic immune system development in newborn children. Cell 174, 1277–1292 e1214 (2018).
Hill, D. L. et al. Immune system development varies according to age, location, and anemia in African children. Sci. Transl Med. 12, eaaw9522 (2020).
Marchant, A. et al. Mature CD8+ T lymphocyte response to viral infection during fetal life. J. Clin. Invest. 111, 1747–1755 (2003).
Karrer, U. et al. Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J. Immunol. 170, 2022–2029 (2003).
Munks, M. W. et al. Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J. Immunol. 177, 450–458 (2006).
Rolot, M. et al. Helminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection. Nat. Commun. 9, 4516 (2018).
Lin, J. S. et al. Virtual memory CD8 T cells expanded by helminth infection confer broad protection against bacterial infection. Mucosal Immunol. 12, 258–264 (2019).
Reese, T. A. et al. Sequential infection with common pathogens promotes human-like immune gene expression and altered vaccine response. Cell Host Microbe 19, 713–719 (2016).
Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).
Zanvit, P. et al. Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis. Nat. Commun. 6, 8424 (2015).
Kirjavainen, P. V. et al. Farm-like indoor microbiota in non-farm homes protects children from asthma development. Nat. Med. 25, 1089–1095 (2019).
Bach, J. F. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat. Rev. Immunol. 18, 105–120 (2018).
Sureshchandra, S., Marshall, N. E. & Messaoudi, I. Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming. J. Leukoc. Biol. 106, 1035–1050 (2019).
Kanneganti, T. D. & Dixit, V. D. Immunological complications of obesity. Nat. Immunol. 13, 707–712 (2012).
Iyer, S. S. et al. Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells. J. Immunol. 188, 77–84 (2012).
Chatraw, J. H., Wherry, E. J., Ahmed, R. & Kapasi, Z. F. Diminished primary CD8 T cell response to viral infection during protein energy malnutrition in mice is due to changes in microenvironment and low numbers of viral-specific CD8 T cell precursors. J. Nutr. 138, 806–812 (2008).
van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).
Kongsbak, M., Levring, T. B., Geisler, C. & von Essen, M. R. The vitamin d receptor and T cell function. Front. Immunol. 4, 148 (2013).
Vanhee, S. et al. Lin28b controls a neonatal to adult switch in B cell positive selection. Sci. Immunol. 4, (2019).
Hardy, R. R. & Hayakawa, K. A developmental switch in B lymphopoiesis. Proc. Natl Acad. Sci. USA 88, 11550–11554 (1991).
Kantor, A. B., Stall, A. M., Adams, S., Herzenberg, L. A. & Herzenberg, L. A. Differential development of progenitor activity for three B-cell lineages. Proc. Natl Acad. Sci. USA 89, 3320–3324 (1992).
McGrath, K. E., Frame, J. M. & Palis, J. Early hematopoiesis and macrophage development. Semin. Immunol. 27, 379–387 (2015).
Perdiguero, E. G. & Geissmann, F. The development and maintenance of resident macrophages. Nat. Immunol. 17, 2–8 (2016).
Schneider, C. et al. Tissue-resident group 2 innate lymphoid cells differentiate by layered ontogeny and in situ perinatal priming. Immunity 50, 1425–1438 e1425 (2019).
Tieppo, P. et al. The human fetal thymus generates invariant effector gammadelta T cells. J. Exp. Med. 217, 20190580 (2020).
Ikuta, K. et al. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874 (1990).
Boursalian, T. E., Golob, J., Soper, D. M., Cooper, C. J. & Fink, P. J. Continued maturation of thymic emigrants in the periphery. Nat. Immunol. 5, 418–425 (2004).
Priyadharshini, B., Welsh, R. M., Greiner, D. L., Gerstein, R. M. & Brehm, M. A. Maturation-dependent licensing of naive T cells for rapid TNF production. PLoS One 5, e15038 (2010).
Hussain, T. & Quinn, K. M. Similar but different: virtual memory CD8 T cells as a memory-like cell population. Immunol. Cell Biol. 97, 675–684 (2019).
Opiela, S. J., Koru-Sengul, T. & Adkins, B. Murine neonatal recent thymic emigrants are phenotypically and functionally distinct from adult recent thymic emigrants. Blood 113, 5635–5643 (2009).
Yuan, J., Nguyen, C. K., Liu, X., Kanellopoulou, C. & Muljo, S. A. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335, 1195–1200 (2012).
Kim, I., Saunders, T. L. & Morrison, S. J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470–483 (2007).
Bonati, A. et al. T-cell receptor beta-chain gene rearrangement and expression during human thymic ontogenesis. Blood 79, 1472–1483 (1992).
Rufer, N. et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J. Exp. Med. 190, 157–167 (1999).
Hale, J. S., Boursalian, T. E., Turk, G. L. & Fink, P. J. Thymic output in aged mice. Proc. Natl Acad. Sci. USA 103, 8447–8452 (2006).
Elder, R. W. et al. Immunologic aging in adults with congenital heart disease: does infant sternotomy matter? Pediatr. Cardiol. 36, 1411–1416 (2015).
Steinmann, G. G., Klaus, B. & Muller-Hermelink, H. K. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand. J. Immunol. 22, 563–575 (1985).
Zhang, X. et al. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus. Sci. Transl Med. 6, 238ra272 (2014).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Immunology thanks T. Burt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Davenport, M.P., Smith, N.L. & Rudd, B.D. Building a T cell compartment: how immune cell development shapes function. Nat Rev Immunol 20, 499–506 (2020). https://doi.org/10.1038/s41577-020-0332-3
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41577-020-0332-3
This article is cited by
-
Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral Treg cell differentiation
Nature Immunology (2024)
-
Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses
Nature Immunology (2023)
-
A standardized metric to enhance clinical trial design and outcome interpretation in type 1 diabetes
Nature Communications (2023)
-
Immunization of preterm infants: current evidence and future strategies to individualized approaches
Seminars in Immunopathology (2022)
-
Naturalizing mouse models for immunology
Nature Immunology (2021)
