Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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). This study demonstrates that naive T cell maintenance occurs fundamentally differently in mice and humans.
Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).
Gibbons, D. et al. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat. Med. 20, 1206–1210 (2014). This study demonstrates that T cells from newborn babies can respond to activation by expressing high levels of IL-8.
Takada, K. & Jameson, S. C. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9, 823–832 (2009).
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).
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).
Fink, P. J. The biology of recent thymic emigrants. Annu. Rev. Immunol. 31, 31–50 (2013).
Haines, C. J. et al. Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. J. Exp. Med. 206, 275–285 (2009).
Kohler, S. et al. Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur. J. Immunol. 35, 1987–1994 (2005).
Kwan, A. et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA 312, 729–738 (2014).
Muraro, P. A. et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J. Exp. Med. 201, 805–816 (2005).
van der Spek, J., Groenwold, R. H., van der Burg, M. & van Montfrans, J. M. TREC based newborn screening for severe combined immunodeficiency disease: a systematic review. J. Clin. Immunol. 35, 416–430 (2015).
Ye, P. & Kirschner, D. E. Measuring emigration of human thymocytes by T-cell receptor excision circles. Crit. Rev. Immunol. 22, 483–497 (2002).
Douek, D. C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998).
Hazenberg, M. D. et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat. Med. 6, 1036–1042 (2000).
Hazenberg, M. D., Verschuren, M. C., Hamann, D., Miedema, F. & van Dongen, J. J. T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J. Mol. Med. 79, 631–640 (2001).
Kilpatrick, R. D. et al. Homeostasis of the naive CD4+ T cell compartment during aging. J. Immunol. 180, 1499–1507 (2008).
Kimmig, S. et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J. Exp. Med. 195, 789–794 (2002).
Kohler, S. & Thiel, A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood 113, 769–774 (2009).
Bains, I., Yates, A. J. & Callard, R. E. Heterogeneity in thymic emigrants: implications for thymectomy and immunosenescence. PLoS ONE 8, e49554 (2013).
van den Broek, T. et al. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells. J. Clin. Invest. 126, 1126–1136 (2016).
Fornasa, G. et al. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. J. Immunol. 184, 5485–5492 (2010).
Vrisekoop, N. T-cell dynamics in healthy and HIV-infected individuals Ch. 7 Thesis, Utrecht Univ. (2007).
McFarland, R. D., Douek, D. C., Koup, R. A. & Picker, L. J. Identification of a human recent thymic emigrant phenotype. Proc. Natl Acad. Sci. USA 97, 4215–4220 (2000).
Das, A. et al. Adaptive from innate: human IFN-gamma+CD4+ T cells can arise directly from CXCL8-producing recent thymic emigrants in babies and adults. J. Immunol. 199, 1696–1705 (2017).
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).
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).
van der Geest, K. S. et al. Low-affinity TCR engagement drives IL-2-dependent post-thymic maintenance of naive CD4+ T cells in aged humans. Aging Cell 14, 744–753 (2015). This study demonstrates further naive T cell heterogeneity by the expression of CD25.
Pekalski, M. L. et al. Postthymic expansion in human CD4 naive T cells defined by expression of functional high-affinity IL-2 receptors. J. Immunol. 190, 2554–2566 (2013).
Berkley, A. M., Hendricks, D. W., Simmons, K. B. & Fink, P. J. Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci. J. Immunol. 190, 6180–6186 (2013).
Cunningham, C. A., Bergsbaken, T. & Fink, P. J. Cutting edge: defective aerobic glycolysis defines the distinct effector function in antigen-activated CD8+ recent thymic emigrants. J. Immunol. 198, 4575–4580 (2017).
LaMere, S. A. et al. H3K27 methylation dynamics during CD4 T cell activation: regulation of JAK/STAT and IL12RB2 expression by JMJD3. J. Immunol. 199, 3158–3175 (2017).
Durek, P. et al. Epigenomic profiling of human CD4+ T cells supports a linear differentiation model and highlights molecular regulators of memory development. Immunity 45, 1148–1161 (2016).
Moskowitz, D. M. et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2, eaag0192 (2017).
Altorok, N. et al. Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjogren’s syndrome. Arthritis Rheumatol. 66, 731–739 (2014).
Coit, P. et al. Epigenetic reprogramming in naive CD4+ T cells favoring T cell activation and non-Th1 effector T cell immune response as an early event in lupus flares. Arthritis Rheumatol. 68, 2200–2209 (2016).
Heninger, A. K. et al. A divergent population of autoantigen-responsive CD4+ T cells in infants prior to beta cell autoimmunity. Sci. Transl Med. 9, eaaf8848 (2017).
Houston, E. G. Jr, Higdon, L. E. & Fink, P. J. Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool. Proc. Natl Acad. Sci. USA 108, 5366–5371 (2011).
Berzins, S. P., Boyd, R. L. & Miller, J. F. The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J. Exp. Med. 187, 1839–1848 (1998).
Berzins, S. P., Godfrey, D. I., Miller, J. F. & Boyd, R. L. A central role for thymic emigrants in peripheral T cell homeostasis. Proc. Natl Acad. Sci. USA 96, 9787–9791 (1999).
van Hoeven, V. et al. Dynamics of recent thymic emigrants in young adult mice. Front. Immunol. 8, 933 (2017).
Dong, J. et al. Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus. PLoS ONE 8, e56378 (2013).
Houston, E. G. Jr & Fink, P. J. MHC drives TCR repertoire shaping, but not maturation, in recent thymic emigrants. J. Immunol. 183, 7244–7249 (2009).
Hogan, T., Gossel, G., Yates, A. J. & Seddon, B. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice. Proc. Natl Acad. Sci. USA 112, E6917–E6926 (2015).
Di Rosa, F. & Pabst, R. The bone marrow: a nest for migratory memory T cells. Trends Immunol. 26, 360–366 (2005).
Thome, J. J. et al. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat. Med. 22, 72–77 (2016).This study reveals early-life T cell distribution and function in different tissue compartments.
Lewis, M., Tarlton, J. F. & Cose, S. Memory versus naive T-cell migration. Immunol. Cell Biol. 86, 226–231 (2008).
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). This study reveals long-term maintenance of human naive T cells in lymphoid tissues with site-specific clonal expansions of naive T cells.
Wong, M. T. et al. A high-dimensional atlas of human T cell diversity reveals tissue-specific trafficking and cytokine signatures. Immunity 45, 442–456 (2016).
Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal influenza—United States, 1976–2007. MMWR Morb. Mortal. Wkly Rep. 59, 1057–1062 (2010).
Gardner, P. & Pabbatireddy, S. Vaccines for women age 50 and older. Emerg. Infect. Dis. 10, 1990–1995 (2004).
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).
Westera, L. et al. Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover. Aging Cell 14, 219–227 (2015).
Tsukamoto, H., Huston, G. E., Dibble, J., Duso, D. K. & Swain, S. L. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J. Immunol. 185, 4535–4544 (2010).
Sauce, D. et al. Lymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults. J. Immunol. 189, 5541–5548 (2012).
Cicin-Sain, L. et al. Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc. Natl Acad. Sci. USA 104, 19960–19965 (2007).
Gardner, I. D. The effect of aging on susceptibility to infection. Rev. Infect. Dis. 2, 801–810 (1980).
Miller, R. A. The aging immune system: primer and prospectus. Science 273, 70–74 (1996).
Akbar, A. N. & Fletcher, J. M. Memory T cell homeostasis and senescence during aging. Curr. Opin. Immunol. 17, 480–485 (2005).
Haynes, L., Eaton, S. M., Burns, E. M., Randall, T. D. & Swain, S. L. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc. Natl Acad. Sci. USA 100, 15053–15058 (2003).
Britanova, O. V. et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192, 2689–2698 (2014).
Britanova, O. V. et al. Dynamics of individual T cell repertoires: from cord blood to centenarians. J. Immunol. 196, 5005–5013 (2016).
Shifrut, E. et al. CD4(+) T cell-receptor repertoire diversity is compromised in the spleen but not in the bone marrow of aged mice due to private and sporadic clonal expansions. Front. Immunol. 4, 379 (2013).
Gibson, K. L. et al. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8, 18–25 (2009).
Qi, Q. et al. Diversity and clonal selection in the human T-cell repertoire. Proc. Natl Acad. Sci. USA 111, 13139–13144 (2014). This study demonstrates that the TCR repertoire of naive T cells only modestly decreases during healthy ageing.
Ferrando-Martinez, S. et al. Age-related deregulation of naive T cell homeostasis in elderly humans. Age 33, 197–207 (2011).
Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518–1524 (2012).
Adkins, B., Leclerc, C. & Marshall-Clarke, S. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553–564 (2004).
Galindo-Albarran, A. O. et al. CD8+ T cells from human neonates are biased toward an innate immune response. Cell Rep. 17, 2151–2160 (2016). This study demonstrates that neonatal CD8 T cells have a distinct epigenetic landscape that is biased towards an innate immune response.
Crespo, M. et al. 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, 136–143 (2012).
Alexander-Miller, M. A. Vaccines against respiratory viral pathogens for use in neonates: opportunities and challenges. J. Immunol. 193, 5363–5369 (2014).
Dowling, D. J. et al. TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth. JCI Insight 2, e91020 (2017).
Heining, C. et al. Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients. Bone Marrow Transplant. 39, 613–622 (2007).
Ringhoffer, S., Rojewski, M., Dohner, H., Bunjes, D. & Ringhoffer, M. T-cell reconstitution after allogeneic stem cell transplantation: assessment by measurement of the sjTREC/betaTREC ratio and thymic naive T cells. Haematologica 98, 1600–1608 (2013).
Alho, A. C. et al. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood 127, 646–657 (2016).
Cieri, N. et al. Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation. Blood 125, 2865–2874 (2015).
Roberto, A. et al. Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation. Blood 125, 2855–2864 (2015).
Thiel, A. et al. Direct assessment of thymic reactivation after autologous stem cell transplantation. Acta Haematol. 119, 22–27 (2008).
Azevedo, R. I. et al. Long-term immune reconstitution of naive and memory T cell pools after haploidentical hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 19, 703–712 (2013).
Douek, D. C. et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875–1881 (2000).
Hazenberg, M. D. et al. T-Cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood 99, 3449–3453 (2002).
Kanakry, C. G. et al. Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight 1, e86252 (2016).
Bleakley, M. et al. Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells. Blood 115, 4923–4933 (2010).
Distler, E. et al. Alloreactive and leukemia-reactive T cells are preferentially derived from naive precursors in healthy donors: implications for immunotherapy with memory T cells. Haematologica 96, 1024–1032 (2011).
Anderson, B. E. et al. Memory CD4+ T cells do not induce graft-versus-host disease. J. Clin. Invest. 112, 101–108 (2003).
Bleakley, M. et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J. Clin. Invest. 125, 2677–2689 (2015).
Politikos, I. & Boussiotis, V. A. The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation. Blood 124, 3201–3211 (2014).
Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Hsieh, C. S., Lee, H. M. & Lio, C. W. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12, 157–167 (2012).
Moran, A. E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).
Caramalho, I. et al. Human regulatory T-cell development is dictated by interleukin-2 and -15 expressed in a non-overlapping pattern in the thymus. J. Autoimmun. 56, 98–110 (2015).
Caramalho, I., Nunes-Cabaco, H., Foxall, R. B. & Sousa, A. E. Regulatory T-cell development in the human thymus. Front Immunol. 6, 395 (2015).
Fuertes Marraco, S. A. et al. Long-lasting stem cell-like memory CD8+ T cells with a naive-like profile upon yellow fever vaccination. Sci. Transl Med. 7, 282ra48 (2015).
Gattinoni, L., Speiser, D. E., Lichterfeld, M. & Bonini, C. T memory stem cells in health and disease. Nat. Med. 23, 18–27 (2017).
Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).
Ahmed, R. et al. Human stem cell-like memory T cells are maintained in a state of dynamic flux. Cell Rep. 17, 2811–2818 (2016).
Miyama, T. et al. Highly functional T-cell receptor repertoires are abundant in stem memory T cells and highly shared among individuals. Sci. Rep. 7, 3663 (2017).
Pulko, V. et al. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat. Immunol. 17, 966–975 (2016).
Nasi, M. et al. Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell 5, 167–175 (2006).
Collier, F. M. et al. The ontogeny of naive and regulatory CD4(+) T-cell subsets during the first postnatal year: a cohort study. Clin. Transl Immunol. 4, e34 (2015).
Utsuyama, M. et al. Differential age-change in the numbers of CD4+CD45RA+ and CD4+CD29+ T cell subsets in human peripheral blood. Mech. Ageing Dev 63, 57–68 (1992).
Stulnig, T., Maczek, C., Bock, G., Majdic, O. & Wick, G. Reference intervals for human peripheral blood lymphocyte subpopulations from ‘healthy’ young and aged subjects. Int. Arch. Allergy Immunol. 108, 205–210 (1995).
Wertheimer, A. M. et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192, 2143–2155 (2014).
Zhang, L. et al. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J. Exp. Med. 190, 725–732 (1999).
Rickabaugh, T. M. et al. The dual impact of HIV-1 infection and aging on naive CD4 T-cells: additive and distinct patterns of impairment. PLOS One 6, e16459 (2011).
Junge, S. et al. Correlation between recent thymic emigrants and CD31+(PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children. Eur. J. Immunol. 37, 3270–3280 (2007).
Koch, S. et al. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun. Ageing 5, 6 (2008).
Reen, D. J. Activation and functional capacity of human neonatal CD4 T-cells. Vaccine 16, 1401–1408 (1998).
Ikewaki, N., Yamao, H., Kulski, J. K. & Inoko, H. Flow cytometric identification of CD93 expression on naive T lymphocytes (CD4(+)CD45RA (+) cells) in human neonatal umbilical cord blood. J. Clin. Immunol. 30, 723–733 (2010).
Mackall, C. L. & Gress, R. E. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol. Rev. 157, 61–72 (1997).
Mackall, C. L. T-Cell immunodeficiency following cytotoxic antineoplastic therapy: a review. Stem Cells 18, 10–18 (2000).
Akbar, A. N., Timms, A. & Janossy, G. Cellular events during memory T-cell activation in vitro: the UCHL1 (180,000 MW) determinant is newly synthesized after mitosis. Immunology 66, 213–218 (1989).
Michie, C. A., McLean, A., Alcock, C. & Beverley, P. C. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265 (1992).
Picker, L. J. et al. Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition. J. Immunol. 150, 1105–1121 (1993).
Trowbridge, I. S. & Thomas, M. L. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu. Rev. Immunol. 12, 85–116 (1994).
Forster, R., Davalos-Misslitz, A. C. & Rot, A. CCR7 and its ligands: balancing immunity and tolerance. Nat. Rev. Immunol. 8, 362–371 (2008).
Hengel, R. L. et al. Cutting edge: L-selectin (CD62L) expression distinguishes small resting memory CD4+ T cells that preferentially respond to recall antigen. J. Immunol. 170, 28–32 (2003).
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).
Warnock, R. A., Askari, S., Butcher, E. C. & von Andrian, U. H. Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J. Exp. Med. 187, 205–216 (1998).
Marelli-Berg, F. M., Clement, M., Mauro, C. & Caligiuri, G. An immunologist’s guide to CD31 function in T-cells. J. Cell Sci. 126, 2343–2352 (2013).
Camerini, D., Walz, G., Loenen, W. A., Borst, J. & Seed, B. The T cell activation antigen CD27 is a member of the nerve growth factor/tumor necrosis factor receptor gene family. J. Immunol. 147, 3165–3169 (1991).
De Jong, R. et al. The CD27- subset of peripheral blood memory CD4+ lymphocytes contains functionally differentiated T lymphocytes that develop by persistent antigenic stimulation in vivo. Eur. J. Immunol. 22, 993–999 (1992).
Ferrando-Martinez, S., Ruiz-Mateos, E. & Leal, M. CD27 and CCR7 expression on naive T cells, are both necessary? Immunol. Lett. 127, 157–158 (2010).
Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).
Romero, P. et al. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J. Immunol. 178, 4112–4119 (2007).
Rufer, N. et al. Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions. Blood 102, 1779–1787 (2003).
Schiott, A., Lindstedt, M., Johansson-Lindbom, B., Roggen, E. & Borrebaeck, C. A. CD27- CD4+ memory T cells define a differentiated memory population at both the functional and transcriptional levels. Immunology 113, 363–370 (2004).
Borthwick, N. J. et al. Lymphocyte activation in HIV-1 infection. II. Functional defects of CD28- T cells. AIDS 8, 431–441 (1994).
Fagnoni, F. F. et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology 88, 501–507 (1996).
Posnett, D. N., Sinha, R., Kabak, S. & Russo, C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammapathy”. J. Exp. Med. 179, 609–618 (1994).
Saukkonen, J. J., Kornfeld, H. & Berman, J. S. Expansion of a CD8+CD28- cell population in the blood and lung of HIV-positive patients. J. Acquir. Immune Def. Syndr. 6, 1194–1204 (1993).
Sfikakis, P. P. et al. CD28 expression on T cell subsets in vivo and CD28-mediated T cell response in vitro in patients with rheumatoid arthritis. Arthritis Rheum. 38, 649–654 (1995).
Strioga, M., Pasukoniene, V. & Characiejus, D. CD8+CD28- and CD8+CD57+ T cells and their role in health and disease. Immunology 134, 17–32 (2011).
The authors apologize to those colleagues whose relevant work was not included in this Review owing to space constraints. The authors thank R. de Boer, M. Hazenberg and L. Meyaard for critically reading the manuscript and for helpful comments and A. Boltjes for support with the figures.
Nature Reviews Immunology thanks R. Kedl and the other anonymous reviewer(s), for their contribution to the peer review of this work.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The condition of having an abnormally low level of lymphocytes in the circulation.
- Haematopoietic stem cell transplantation
(HSCT). Treatment of recipients with irradiation and/or chemotherapy followed by the infusion of cells containing haematopoietic stem and progenitor cells with or without immune cells derived from individuals of the same species.
- Homeostatic proliferation
This term can refer to two different phenomena: the steady-state maintenance of T cells through self-renewal (minimal division) and the process by which T cells in lymphopenic conditions rapidly proliferate to reconstitute the T cell pool, also called lymphopenia-induced proliferation.
- Virtual memory T cells
Antigen-inexperienced memory-phenotype T cells, which may be induced by T cell receptor cross reactivity, low-affinity peptide and/or MHC ligands and certain cytokines.
- Mature naive T cells
Naive T cells that have matured in secondary lymphoid organs following thymic egress and are no longer recent thymic emigrants.
- T cell receptor excision circles
(TRECs). Small, stable circles of DNA excised during T cell receptor gene rearrangement in the thymus.
- Simpson’s diversity index
A measure of diversity that takes into account the number of clones present, as well as the relative abundance of each clone.
- Repertoire skewedness
The extent to which a repertoire deviates from a situation where all clones occur equally frequently.
- Thymic output
The amount of T cells that successfully exit the thymus into the periphery after intrathymic selection.
- Graft-versus-host disease
(GVHD). An inflammatory complication following the transplantation of stem cells or organs to a genetically different person caused by donor immune cells that recognize the recipient’s cells and tissues as foreign.
About this article
Cite this article
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). https://doi.org/10.1038/s41577-018-0001-y
Nature Reviews Immunology (2021)
Nature Reviews Immunology (2021)
Clinical Characteristics of Paediatric Hyperinflammatory Syndrome in the Era of Corona Virus Disease 2019 (COVID-19)
Indian Journal of Clinical Biochemistry (2021)
A very low thymus function identifies patients with substantial increased risk for long-term mortality after kidney transplantation
Immunity & Ageing (2020)
Multi-HLA class II tetramer analyses of citrulline-reactive T cells and early treatment response in rheumatoid arthritis
BMC Immunology (2020)