Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 6/2008

01-11-2008

Molecular Mechanisms of Regulatory T Cell Development

Author: Talal Chatila

Published in: Journal of Clinical Immunology | Issue 6/2008

Login to get access

Abstract

Background

CD4+CD25+ natural regulatory T (nTR) lymphocytes represent a distinct thymus-derived T cell lineage that serves to establish immunological tolerance in the periphery. The discovery of Foxp3 as a transcription factor essential to the differentiation of CD4+CD25+ TR cells enabled detailed studies into the molecular mechanisms of TR cell development, peripheral homeostasis, and effector functions.

Discussion

Comparative analysis of Foxp3+ nTR cells and nTR cell precursors expressing a functionally inactive Foxp3 mutant protein indicated that while Foxp3 is not essential for nTR cell development in the thymus, it is critical to the peripheral homeostasis and suppressor functions of nTR cells. A second subset of Foxp3+ regulatory T cells can be induced de novo from conventional CD4+ Foxp3− T cells both in vitro, upon antigenic stimulation in the presence of transforming growth factor β and interleukin-2, and in vivo. Like nTR cells, the induced regulatory T (iTR) cells are also dependent on Foxp3 expression for their suppressor function. It is likely that nTR and iTR cells serve nonredundant functions in the maintenance of immunological tolerance.
Literature
1.
Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol 2005;116:949–59. quiz 960.PubMedCrossRef
2.
Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and FOXP3 in human diseases. J Allergy Clin Immunol 2007;120:227–35. quiz 236–7.PubMedCrossRef
3.
Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol 2007;8:457–62.PubMedCrossRef
4.
Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002;2:389–400.PubMed
5.
Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188:287–96.PubMedCrossRef
6.
Xu D, Liu H, Komai-Koma M, Campbell C, McSharry C, Alexander J, et al. CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J Immunol 2003;170:394–9.PubMed
7.
Stassen M, Jonuleit H, Muller C, Klein M, Richter C, Bopp T, et al. Differential regulatory capacity of CD25+ T regulatory cells and preactivated CD25+ T regulatory cells on development, functional activation, and proliferation of Th2 cells. J Immunol 2004;173:267–74.PubMed
8.
Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT. CD4+CD25+T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 2003;198:889–901.PubMedCrossRef
9.
Clark LB, Appleby MW, Brunkow ME, Wilkinson JE, Ziegler SF, Ramsdell F. Cellular and molecular characterization of the scurfy mouse mutant. J Immunol 1999;162:2546–54.PubMed
10.
Blair PJ, Bultman SJ, Haas JC, Rouse BT, Wilkinson JE, Godfrey VL. CD4+CD8-T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J Immunol 1994;153:3764–74.PubMed
11.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330–6.PubMedCrossRef
12.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057–61.PubMedCrossRef
13.
Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4:337–42.PubMedCrossRef
14.
Liston A, Farr AG, Chen Z, Benoist C, Mathis D, Manley NR, et al. Lack of Foxp3 function and expression in the thymic epithelium. J Exp Med 2007;204:475–80.PubMedCrossRef
15.
Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007;445:771–5.PubMedCrossRef
16.
Lin W, Haribhai D, Relland LM, Truong N, Carlson MR, Williams CB, et al. Regulatory T cell development in the absence of functional Foxp3. Nat Immunol 2007;8:359–68.PubMedCrossRef
17.
Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome [In Process Citation]. J Clin Invest 2000;106:R75–81.PubMedCrossRef
18.
Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007;8:277–84.PubMedCrossRef
19.
Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, et al. Thymic selection of CD4+CD25+regulatory T cells induced by an agonist self-peptide. Nat Immunol 2001;2:301–6.PubMedCrossRef
20.
21.
Jordan MS, Riley MP, von Boehmer H, Caton AJ. Anergy and suppression regulate CD4+ T cell responses to a self peptide. Eur J Immunol 2000;30:136–44.PubMedCrossRef
22.
Kawahata K, Misaki Y, Yamauchi M, Tsunekawa S, Setoguchi K, Miyazaki J, et al. Generation of CD4+CD25+ regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression. J Immunol 2002;168:4399–405.PubMed
23.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells [comment]. Nat Immunol 2003;4:330–6.PubMedCrossRef
24.
Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK. Antigen-dependent proliferation of CD4+CD25+ regulatory T cells in vivo. J Exp Med 2003;198:249–58.PubMedCrossRef
25.
Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001;2:816–22.PubMedCrossRef
26.
Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio CW, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 2008;28:112–21.PubMedCrossRef
27.
Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity 2008;28:100–11.PubMedCrossRef
28.
Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+CD4+ T cell receptors. Immunity 2004;21:267–77.PubMedCrossRef
29.
Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006;7:401–10.PubMedCrossRef
30.
Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 2006;25:249–59.PubMedCrossRef
31.
Wong J, Mathis D, Benoist C. TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets. J Exp Med 2007;204:2039–45.PubMedCrossRef
32.
van Santen HM, Benoist C, Mathis D. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J Exp Med 2004;200:1221–30.PubMedCrossRef
33.
Pacholczyk R, Kern J, Singh N, Iwashima M, Kraj P, Ignatowicz L. Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity 2007;27:493–504.PubMedCrossRef
34.
Pennington DJ, Silva-Santos B, Silberzahn T, Escorcio-Correia M, Woodward MJ, Roberts SJ, et al. Early events in the thymus affect the balance of effector and regulatory T cells. Nature 2006;444:1073–7.PubMedCrossRef
35.
Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22:329–41.PubMedCrossRef
36.
Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A. Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nat Immunol 2002;3:33–41.PubMedCrossRef
37.
Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med 2005;202:1387–97.PubMedCrossRef
38.
Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T, et al. Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 2006;18:1197–209.PubMedCrossRef
39.
Glimcher LH, Townsend MJ, Sullivan BM, Lord GM. Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol 2004;4:900–11.PubMedCrossRef
40.
Kim CH, Kunkel EJ, Boisvert J, Johnston B, Campbell JJ, Genovese MC, et al. Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J Clin Invest 2001;107:595–601.PubMedCrossRef
41.
Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007;445:931–5.PubMedCrossRef
42.
Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 2007;445:936–40.PubMedCrossRef
43.
Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 2007;27:786–800.PubMed
44.
45.
Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 2007;13:108–16.PubMedCrossRef
46.
Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+ CD25+ Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 2007;8:1353–62.PubMedCrossRef
47.
Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875–86.PubMedCrossRef
48.
Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 2004;172:5149–53.PubMed
49.
Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-beta to convert naive CD4+CD25− cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 2007;178:2018–27.PubMed
50.
Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol 2007;178:4022–6.PubMed
51.
Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA. Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 2005;115:1923–33.PubMedCrossRef
52.
Apostolou I, von Boehmer H. In vivo instruction of suppressor commitment in naive T cells. J Exp Med 2004;199:1401–8.PubMedCrossRef
53.
Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007;5:e38.PubMedCrossRef
54.
Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 2007;204:1765–74.PubMedCrossRef
55.
Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 2007;204:1757–64.PubMedCrossRef
56.
Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007;317:256–60.PubMedCrossRef
57.
Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 2007;204:1775–85.PubMedCrossRef
58.
Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol 2007;179:3724–33.PubMed
59.
Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach EM, O’Shea JJ. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 2008;111:1013–20.PubMedCrossRef
Metadata
Title
Molecular Mechanisms of Regulatory T Cell Development
Author
Talal Chatila
Publication date
01-11-2008
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 6/2008
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-008-9241-0

Other articles of this Issue 6/2008

Journal of Clinical Immunology 6/2008 Go to the issue

ReviewPaper

Role of Endogenous and Induced Regulatory T Cells During Infections

ReviewPaper

TGF-β and Regulatory T Cell in Immunity and Autoimmunity

ReviewPaper

IL-2 Family of Cytokines in T Regulatory Cell Development and Homeostasis

ReviewPaper

Limited T-Cell Receptor Diversity Predisposes to Th2 Immunopathology: Involvement of Tregs and Conventional CD4 T Cells

ReviewPaper

The IL-2/CD25 Pathway Determines Susceptibility to T1D in Humans and NOD Mice

ReviewPaper

Regulation and Privilege in Transplantation Tolerance
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits