Abstract
T regulatory cells (Treg), defined by the transcription factor FoxP3, play an essential role in immune regulation and are required throughout life. Treg are generated either directly from the thymus or via peripheral T cells which acquire regulatory phenotype when activated in the presence of factors such as TGFβ. The relative contribution of these two populations over the life course is unclear. The number of T regulatory cells increases with age in both mice and humans, and CD4+FoxP3+ cells represent around 4.4% and 5.8% of the CD4+ repertoire in younger (<30 years) and older people (>70 years), respectively. This may relate to increased peripheral conversion from effector cells, methylation at regulatory elements of FoxP3, or reduced expression of apoptotic proteins such as Bim. Importantly, the function of T regulatory cells does not appear to deteriorate with age. There is increasing interest in the potential role of Treg cells in the development of immune senescence. Antibody-mediated CD25 cell depletion can improve immune responses and clinical protection to influenza challenge in aged mice, but translation of these findings to humans has not yet been undertaken. Depletion of Treg cells is a therapeutic aim in the treatment of cancer but complicated by the development of autoimmunity. In addition, cohort studies suggest that increased numbers of regulatory cells may be associated with improved overall survival in older people. T regulatory cells play an essential and complex role in the immune homeostasis of older people, but optimal approaches to therapeutic manipulation are currently uncertain.
References
Abbas AK, Trotta E, Simeonov DR, Marson A, Bluestone JA (2018) Revisiting IL-2: biology and therapeutic prospects. Sci Immunol 3(25):eaat1482
Allan SE et al (2007) Activation-induced FOXP3 in human T-effector cells does not suppress proliferation or cytokine production. Int Immunol 19(4):345–354
Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, Henry JY, Spain L, Ben Aissa A, Georgiou A, Wong YNS, Smith M, Strauss D, Hayes A, Nicol D, O’Brien T, Mårtensson L, Ljungars A, Teige I, Frendéus B, TRACERx Melanoma, TRACERx Renal, TRACERx Lung consortia, Pule M, Marafioti T, Gore M, Larkin J, Turajlic S, Swanton C, Peggs KS, Quezada SA (2018) Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33(4):649–663
Arruvito L, Payaslian F, Baz P, Podhorzer A, Billordo A, Pandolfi J et al (2014) Identification and clinical relevance of naturally occurring human CD8+HLA-DR+ regulatory T cells. J Immunol 193(9):4469–4476
Aspinall R (2006) T-cell development, ageing and Interleukin-7. Mech Ageing Dev 127(6):572–578
Atarashi K, Umesaki Y, Honda K (2011) Microbiotal influence on T cell subset development. Semin Immunol 23:146–153
Bektas A, Schurman SH, Sen R, Ferrucci L (2017) Human T cell immunosenescence and inflammation in aging. J Leukoc Biol 102(4):977–988
Blais ME et al (2008) Why T-cells of thymic versus extrathymic origin are functionally different. J Immunol 180(4):2299–2312
Borsellino G et al (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg-cells: hydrolysis of extracellular ATP and immune suppression. Blood 110(4):1225–1232
Brodin P, Jojic V, Gao T, Bhattacharya S, Angel CJ, Furman D, Shen-Orr S, Dekker CL, Swan GE, Butte AJ, Maecker HT, Davis MM (2015) Variation in the human immune system is largely driven by non-heritable influences. Cell 160(1–2):37–47
Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27(1):68–73
Bryl E, Witkowski JM (2004) Decreased proliferative capability of CD4(+) cells of elderly people is associated with faster loss of activation-related antigens and accumulation of regulatory T-cells. Exp Gerontol 39(4):587–595
Carpentier M, Chappert P, Kuhn C et al (2013) Extrathymic induction of Foxp3+ regulatory T cells declines with age in a T-cell intrinsic manner. Eur J Immunol 43:2598–2604
Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, Plas DR, Hildeman DA (2011) A major role for Bim in regulatory T cell homeostasis. J Immunol 186(1):156–163
Czesnikiewicz-Guzik M et al (2008) T-cell subset-specific susceptibility to aging. Clin Immunol 127(1):107–118
Darrigues J, van Meerwijk JPM, Romagnoli P (2018) Age-dependent changes in regulatory T lymphocyte development and function: a mini-review. Gerontology 64(1):28–35
Dejaco C, Duftner C, Schirmer M (2006) Are regulatory T-cells linked with aging? Exp Gerontol 41(4):339–345
Derhovanessian E, Chen S, Maier AB, Hähnel K, de Craen AJ, Roelofs H, Westendorp R, Pawelec G (2015) CCR4+ regulatory T cells accumulate in the very elderly and correlate with superior 8-year survival. J Gerontol A Biol Sci Med Sci 70(8):917–923
Dorf ME, Benacerraf B (1984) Suppressor cells and immuno-regulation. Annu Rev Immunol 2:127–157
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T-cells. Nat Immunol 4(4):330–336
Garg SK, Delaney C, Toubai T, Ghosh A, Reddy P, Banerjee R, Yung R (2014) Aging is associated with increased regulatory T-cell function. Aging Cell 13(3):441–448
Goldeck D, Theeten H, Hassouneh F, Oettinger L, Wistuba-Hamprecht K, Cools N, Tsitsilonis OE, Pawelec G (2017) Frequencies of peripheral immune cells in older adults following seasonal influenza vaccination with an adjuvanted vaccine. Vaccine 35(34):4330–4338
Goronzy JJ, Weyand CM (2012) Immune aging and autoimmunity. Cell Mol Life Sci 69(10):1615–1623
Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, Nayak L, Moss PA (2005) The number of human peripheral blood CD4+ CD25high regulatory T- cells increases with age. Clin Exp Immunol 140(3):540–546
Han GM, Zhao B, Jeyaseelan S, Feng JM (2009) Age-associated parallel increase of Foxp3(+)CD4(+) regulatory and CD44(+)CD4(+) memory T cells in SJL/J mice. Cell Immunol 258(2):188–196
Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, Ziegelbauer J, Yassai M, Li SH, Relland LM, Wise PM, Chen A, Zheng YQ, Simpson PM, Gorski J, Salzman NH, Hessner MJ, Chatila TA, Williams CB (2011) A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35(1):109–122
Harpaz I, Bhattacharya U, Elyahu Y, Strominger I, Monsonego A (2017) Old mice accumulate activated effector CD4 T cells refractory to regulatory T cell-induced immunosuppression. Front Immunol 8:283
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T-cell development by the transcription factor Foxp3. Science 299(5609):1057–1061
Hsieh CS et al (2006) An intersection between the self-reactive regulatory and nonregulatory T-cell receptor repertoires. Nat Immunol 7(4):401–410
Hwang KA, Kim HR, Kang I (2009) Aging and human CD4(+) regulatory T cells. Mech Ageing Dev 130(8):509–517
Jagger A, Shimojima Y, Goronzy JJ, Weyand CM (2014) Regulatory T cells and the immune aging process: a mini-review. Gerontology 60(2):130–137
Johnson ND, Wiener HW, Smith AK, Nishitani S, Absher DM, Arnett DK, Aslibekyan S, Conneely KN (2017) Non-linear patterns in age-related DNA methylation may reflect CD4+ T cell differentiation. Epigenetics 12(6):492–503
Kared H et al (2005) Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells. Diabetes 54(1):78–84
Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T-cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8(2):191–197
Kiniwa Y et al (2007) CD8+ Foxp3+ regulatory T-cells mediate immuno-suppression in prostate cancer. Clin Cancer Res 13(23):6947–6958
Kozlowska E et al (2007) Age-related changes in the occurrence and characteristics of thymic CD4(+) CD25(+) T-cells in mice. Immunology 122(3):445–453
Lages CS, Suffia I, Velilla PA, Huang B, Warshaw G, Hildeman DA, Belkaid Y, Chougnet C (2008) Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol 181(3):1835–1848
Larbi A, Pawelec G, Wong SC, Goldeck D, Tai JJ, Fulop T (2011) Impact of age on T cell signaling: a general defect or specific alterations? T Ageing Res Rev 10(3):370–378
Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh CS (2008) Antigen-specific peripheral shaping of the natural regulatory T cell population. J Exp Med 205(13):3105–3117
Lee HM, Bautista JL, Scott-Browne J, Mohan JF, Hsieh CS (2012) A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37(3):475–486
Liston A, Gray DH (2014) Homeostatic control of regulatory T cell diversity. Nat Rev Immunol 14:154–165
Liu W et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T-reg cells. J Exp Med 203(7):1701–1711
Lu L, Barbi J, Pan F (2017) The regulation of immune tolerance by FOXP3. Nat Rev Immunol 17(11):703–717
Lukas Yani S, Keller M, Melzer FL, Weinberger B, Pangrazzi L, Sopper S, Trieb K, Lobina M, Orrù V, Fiorillo E, Cucca F, Grubeck-Loebenstein B (2018) CD8+HLADR+ regulatory T cells change with aging: they increase in number, but lose checkpoint inhibitory molecules and suppressive function. Front Immunol 9:1201
Meloni F et al (2006) Foxp3 expressing CD4+ CD25+ and CD8+CD28- T-regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Hum Immunol 67(1–2):1–12
Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6):899–911
Nakahara M, Nagayama Y, Ichikawa T, Yu L, Eisenbarth GS, Abiru N (2011) The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages. Autoimmunity 44(6):504–510
Nikolich-Žugich J (2014) Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol 193:2622–2629
Nishioka T et al (2006) CD4+CD25+Foxp3+ T-cells and CD4+CD25-Foxp3+ T-cells in aged mice. J Immunol 176(11):6586–6593
Nishioka T, Nishida E, Iida R, Morita A, Shimizu J (2008) In vivo expansion of CD4+Foxp3+ regulatory T cells mediated by GITR molecules. Immunol Lett 121(2):97–104
Oh J, Wang W, Thomas R, Su DM (2017) Capacity of tTreg generation is not impaired in the atrophied thymus. PLoS Biol 15(11):e2003352
Pacholczyk R et al (2006) Origin and T-cell receptor diversity of Foxp3+CD4+CD25+ T-cells. Immunity 25(2):249–259
Plitas G, Rudensky AY (2016) Regulatory T cells: differentiation and function. Cancer Immunol Res 4(9):721–725
Raynor J, Lages CS, Shehata H, Hildeman DA, Chougnet CA (2012) Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol 24(4):482–487
Raynor J, Sholl A, Plas DR et al (2013) IL-15 fosters age-driven regulatory T cell accrual in the face of declining IL-2 levels. Front Immunol 4:161
Raynor J, Karns R, Almanan M, Li KP, Divanovic S, Chougnet CA, Hildeman DA (2015) IL-6 and ICOS antagonize Bim and promote regulatory T cell accrual with age. J Immunol 195(3):944–952
Rosenkranz D et al (2007) Higher frequency of regulatory T-cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol 188(1–2):117–127
Sakaguchi S et al (1995) Immunologic self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164
Seddiki N et al (2006a) Persistence of naive CD45RA+ regulatory T-cells in adult life. Blood 107(7):2830–2838
Seddiki N et al (2006b) Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T-cells. J Exp Med 203(7):1693–1700
Selvaraj RK, Geiger TL (2007) A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta. J Immunol 178(12):7667–7677
Sharma S, Dominguez AL, Lustgarten J (2006) High accumulation of T-regulatory cells prevents the activation of immune responses in aged animals. J Immunol 177(12):8348–8355
Shimizu J, Moriizumi E (2003) CD4+CD25- T-cells in aged mice are hyporesponsive and exhibit suppressive activity. J Immunol 170(4):1675–1682
Sun L, Hurez VJ, Thibodeaux SR, Kious MJ, Liu A, Lin P, Murthy K, Pandeswara S, Shin T, Curiel TJ (2012) Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells. Aging Cell 11(3):509–519
Suzuki M, Jagger AL, Konya C, Shimojima Y, Pryshchep S, Goronzy JJ, Weyand CM (2012) CD8+CD45RA+CCR7+FOXP3+ T cells with immunosuppressive properties: a novel subset of inducible human regulatory T cells. J Immunol 189(5):2118–2130
Thiault N, Darrigues J, Adoue V, Gros M, Binet B, Perals C, Leobon B, Fazilleau N, Joffre OP, Robey EA, van Meerwijk JP, Romagnoli P (2015) Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat Immunol 16(6):628–634
Thomas DC, Mellanby RJ, Phillips JM, Cooke A (2007) An early age-related increase in the frequency of CD4+ Foxp3+ cells in BDC2.5NOD mice. Immunology 121(4):565–576
Trzonkowski P, Szmit E, Myśliwska J, Myśliwski A (2006) CD4+CD25+ T-regulatory cells inhibit cytotoxic activity of CTL and NK-cells in humans-impact of immunosenescence. Clin Immunol 119(3):307–316
van der Geest KS, Abdulahad WH, Tete SM, Lorencetti PG, Horst G, Bos NA, Kroesen BJ, Brouwer E, Boots AM (2014) Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp Gerontol 60:190–196
Vuddamalay Y, van Meerwijk JP (2017) CD28- and CD28lowCD8+ regulatory T cells: of mice and men. Front Immunol 8:31
Vukmanovic-Stejic M et al (2006) Human CD4+ CD25hi Foxp3+ regulatory T-cells are derived by rapid turnover of memory populations in vivo. J Clin Invest 116(9):2423–2433
Walker MR et al (2003) Induction of FoxP3 and acquisition of T-regulatory activity by stimulated human CD4+CD25- T-cells. J Clin Invest 112(9):1437–1443
Wang L, Xie Y, Zhu LJ, Chang TT, Mao YQ, Li J (2010) An association between immunosenescence and CD4(+)CD25(+) regulatory T cells: a systematic review. Biomed Environ Sci 23(4):327–332
Wen Z, Wang X, Dong K, Zhang H, Bu Z, Ye L, Yang C (2017) Blockage of regulatory T cells augments induction of protective immune responses by influenza virus-like particles in aged mice. Microbes Infect 19(12):626–634
Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20
Williams-Bey Y, Jiang J, Murasko DM (2011) Expansion of regulatory T cells in aged mice following influenza infection. Mech Ageing Dev 132(4):163–170
Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E (2002) Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 106(2):190–199
Yadav M, Stephan S, Bluestone JA (2013) Peripherally induced tregs – role in immune homeostasis and autoimmunity. Front Immunol 4:232
Yang E, Zou T, Leichner TM, Zhang SL, Kambayashi T (2014) Both retention and recirculation contribute to long-lived regulatory T-cell accumulation in the thymus. Eur J Immunol 44(9):2712–2720
Zhao L et al (2007) Changes of CD4+CD25+Foxp3+ regulatory T-cells in aged Balb/c mice. J Leukoc Biol 81(6):1386–1394
Zheng SG et al (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 172(9):5213–5221
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this entry
Cite this entry
Moss, P. (2019). The Role of T Regulatory Cells in Immune Senescence. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_10-1
Download citation
DOI: https://doi.org/10.1007/978-3-319-64597-1_10-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-64597-1
Online ISBN: 978-3-319-64597-1
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences