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Current Allergy and Asthma Reports
Published in: Current Allergy and Asthma Reports 4/2016

01-04-2016 | Immune Deficiency and Dysregulation (DP Huston and C Kuo, Section Editors)

T Regulatory Cell Biology in Health and Disease

Authors: Fayhan J. Alroqi, Talal A. Chatila

Published in: Current Allergy and Asthma Reports | Issue 4/2016

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Abstract

Regulatory T (Treg) cells that express the transcription factor forkhead box protein P3 (FOXP3) play an essential role in enforcing immune tolerance to self tissues, regulating host-commensal flora interaction, and facilitating tissue repair. Their deficiency and/or dysfunction trigger unbridled autoimmunity and inflammation. A growing number of monogenic defects have been recognized that adversely impact Treg cell development, differentiation, and/or function, leading to heritable diseases of immune dysregulation and autoimmunity. In this article, we review recent insights into Treg cell biology and function, with particular attention to lessons learned from newly recognized clinical disorders of Treg cell deficiency.
Literature
1.
Sleckman BP, Gorman JR, Alt FW. Accessibility control of antigen-receptor variable-region gene assembly: role of cis-acting elements. Annu Rev Immunol. 1996;14:459–81.CrossRefPubMed
2.
Laufer TM, Fan L, Glimcher LH. Self-reactive T cells selected on thymic cortical epithelium are polyclonal and are pathogenic in vivo. J Immunol. 1999;162(9):5078–84.PubMed
3.
Peterson P et al. APECED: a monogenic autoimmune disease providing new clues to self-tolerance. Immunol Today. 1998;19(9):384–6.CrossRefPubMed
4.
5.
6.
Klein L, Jovanovic K. Regulatory T cell lineage commitment in the thymus. Semin Immunol. 2011;23(6):401–9.CrossRefPubMed
7.
Bonomo A et al. Pathogenesis of post-thymectomy autoimmunity. Role of syngeneic MLR-reactive T cells. J Immunol. 1995;154(12):6602–11.PubMed
8.
Asano M et al. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med. 1996;184(2):387–96.CrossRefPubMed
9.
Sakaguchi S et al. 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. 1995;155(3):1151–64.PubMed
10.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6.CrossRefPubMed
11.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.CrossRefPubMed
12.
Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 2007;8(5):457–62.CrossRefPubMed
13.
Bennett CL et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.CrossRefPubMed
14.
Clark LB et al. Cellular and molecular characterization of the scurfy mouse mutant. J Immunol. 1999;162(5):2546–54.PubMed
15.
Komatsu N et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A. 2009;106(6):1903–8.CrossRefPubMedPubMedCentral
16.
Abbas AK et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013;14(4):307–8.CrossRefPubMed
17.
Maynard CL et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nat Immunol. 2007;8(9):931–41.CrossRefPubMed
18.
19.
Takahashi T et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303–10.CrossRefPubMedPubMedCentral
20.
McHugh RS et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002;16(2):311–23.CrossRefPubMed
21.
Miyara M et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911.CrossRefPubMed
22.
Himmel ME et al. Helios+ and Helios− cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol. 2013;190(5):2001–8.CrossRefPubMed
23.
Yadav M et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012;209(10):1713–22. S1-19.CrossRefPubMedPubMedCentral
24.
Zhou X et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009;10(9):1000–7.CrossRefPubMedPubMedCentral
25.•
Komatsu N et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8. This article shows production of pathogenic TH17 cells due to Foxp3 instability and their contribution to the pathogenesis of autoimmunity.CrossRefPubMed
26.
27.
Jordan MS et al. Thymic selection of CD4 + CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol. 2001;2(4):301–6.CrossRefPubMed
28.•
Mahmud SA et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol. 2014;15(5):473–81. This study delineates the importance of the high expression of GITR, OX40, and TNFR2 on Treg cell progenitors to undergo successful maturation.CrossRefPubMedPubMedCentral
29.
Tai X et al. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol. 2005;6(2):152–62.CrossRefPubMed
30.
Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12(3):157–67.PubMed
31.
Gavin MA et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci U S A. 2006;103(17):6659–64.CrossRefPubMedPubMedCentral
32.
33.
34.
Ohkura N et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37(5):785–99.CrossRefPubMed
35.•
Kitagawa Y, Wing JB, Sakaguchi S. Transcriptional and epigenetic control of regulatory T cell development. Prog Mol Biol Transl Sci. 2015;136:1–33. This publication discusses key transcriptional and epigenetic factors that are important for Treg cell genetic profile.CrossRefPubMed
36.•
Kim HJ et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science. 2015;350(6258):334–9. This experimental study provides evidence that Helios is important factor in Treg cell suppressive activity.CrossRefPubMedPubMedCentral
37.
38.
39.••
Charbonnier LM et al. Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat Immunol. 2015;16(11):1162–73. This publication shows the critical role for Notch signaling in controlling peripheral Treg cell function.CrossRefPubMed
40.
Bilate AM, Lafaille JJ. Induced CD4 + Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol. 2012;30:733–58.CrossRefPubMed
41.
Chen W 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(12):1875–86.CrossRefPubMedPubMedCentral
42.
Coombes JL 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(8):1757–64.CrossRefPubMedPubMedCentral
43.
Sun CM et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204(8):1775–85.CrossRefPubMedPubMedCentral
44.
Haribhai D et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 2011;35(1):109–22.CrossRefPubMedPubMedCentral
45.
46.•
Wang S et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity. 2015;43(2):289–303. This study demonstrates the important role for MyD88-dependent microbial sensing by Treg cells in promoting immunological tolerance by anti-microbial IgA responses.CrossRefPubMed
47.•
Kawamoto S et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity. 2014;41(1):152–65. This article reviews the contribution of Foxp3 + T cells in diversification of gut microbiota.
48.•
Pandiyan P, Zhu J. Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells. Cytokine. 2015;76(1):13–24. This study reviews the mechanisms of induction of effector cytokines in Foxp3 + Treg cells.
49.•
Noval Rivas M et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity. 2015;42(3):512–23. Study shows reprogramming of Treg cells into Th2-like cells under the action of IL-4R signaling. Interruption of this process might provide candidate therapeutic strategies in food allergy.CrossRefPubMed
50.
Wing K et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.CrossRefPubMed
51.
52.
Garin MI et al. Galectin-1: a key effector of regulation mediated by CD4 + CD25+ T cells. Blood. 2007;109(5):2058–65.CrossRefPubMed
53.
Grossman WJ et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21(4):589–601.CrossRefPubMed
54.
Pandiyan P et al. CD4 + CD25 + Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007;8(12):1353–62.CrossRefPubMed
55.
Collison LW et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–9.CrossRefPubMed
56.
Li MO et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.CrossRefPubMed
57.
Koch MA et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009;10(6):595–602.CrossRefPubMedPubMedCentral
58.
59.
60.
61.
Rouse BT, Sarangi PP, Suvas S. Regulatory T cells in virus infections. Immunol Rev. 2006;212:272–86.CrossRefPubMed
62.••
Arpaia N et al. A distinct function of regulatory T cells in tissue protection. Cell. 2015;162(5):1078–89. This providing a new role for Treg cells in tissue protection.CrossRefPubMed
63.
Fyhrquist N et al. Foxp3+ cells control Th2 responses in a murine model of atopic dermatitis. J Investig Dermatol. 2012;132(6):1672–80.CrossRefPubMed
64.
Vudattu NK, Herold KC. Delayed anti-CD3 therapy in a mouse heart transplant model induced tolerance and long-term survival of allograft: achieving tolerance. Immunotherapy. 2013;5(11):1173–6.CrossRefPubMed
65.
Ait-Oufella H et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006;12(2):178–80.CrossRefPubMed
66.
Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120(4):744–50. quiz 751–2.CrossRefPubMed
67.
Gambineri E et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol. 2008;122(6):1105–12. e1.CrossRefPubMed
68.•
Kucuk ZY, et al. A challenging undertaking: Stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol. 2015. doi:10.​1016/​j.​jaci.​2015.​09.​030. This publication highlights HSCT long-term outcomes in patients with IPEX syndrome.
69.
Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr. 2013;25(6):708–14.CrossRefPubMedPubMedCentral
70.
Sadlack B et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol. 1995;25(11):3053–9.CrossRefPubMed
71.
Sadlack B et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993;75(2):253–61.CrossRefPubMed
72.
Suzuki H et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science. 1995;268(5216):1472–6.CrossRefPubMed
73.
Snow JW et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J Immunol. 2003;171(10):5042–50.CrossRefPubMed
74.
Sharfe N et al. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A. 1997;94(7):3168–71.CrossRefPubMedPubMedCentral
75.
Caudy AA et al. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007;119(2):482–7.CrossRefPubMed
76.
77.
78.
Fontenot JD et al. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6(11):1142–51.CrossRefPubMed
79.
80.
Maloy KJ, Powrie F. Fueling regulation: IL-2 keeps CD4+ Treg cells fit. Nat Immunol. 2005;6(11):1071–2.CrossRefPubMed
81.
Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006;441(7095):890–3.CrossRefPubMedPubMedCentral
82.
Pipkin ME et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity. 2010;32(1):79–90.CrossRefPubMedPubMedCentral
83.
84.
Cui Y et al. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol. 2004;24(18):8037–47.CrossRefPubMedPubMedCentral
85.
Bernasconi A et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics. 2006;118(5):e1584–92.CrossRefPubMed
86.
Nadeau K, Hwa V, Rosenfeld RG. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J Pediatr. 2011;158(5):701–8.CrossRefPubMed
87.
Bezrodnik L et al. Long-term follow-up of STAT5B deficiency in three argentinian patients: clinical and immunological features. J Clin Immunol. 2015;35(3):264–72.CrossRefPubMed
88.
Kofoed EM et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349(12):1139–47.CrossRefPubMed
89.
90.••
Lo B et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40. It is providing a mechanistic view of LRBA in controlling CTLA4 expression and highlighting response to Abetacept in LRBA deficient patients.CrossRefPubMed
91.••
Charbonnier LM et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol. 2015;135(1):217–27. Study shows increased TFH and decreased TFR cell in LRBA-deficient patients and their implication in the development of autoantibodies.CrossRefPubMedPubMedCentral
92.••
Kuehn HS et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623–7. This article demonstrates that CTLA4 haploinsufficiency in human might present with IPEX like phenotype.CrossRefPubMedPubMedCentral
93.••
Schubert D et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6. This study reported a spectrum of genetic alterations leading to defective CTLA-4 function.CrossRefPubMedPubMedCentral
94.
Lopez-Herrera G et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986–1001.CrossRefPubMedPubMedCentral
95.
Alangari A et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol. 2012;130(2):481–8. e2.CrossRefPubMedPubMedCentral
96.
Serwas NK et al. Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel Dis. 2015;21(1):40–7.CrossRefPubMed
97.•
Revel-Vilk S et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin Immunol. 2015;159(1):84–92. This study emphasizes that LRBA deficiency should be considered in patients presenting with ALPS like phenotype.CrossRefPubMed
98.••
Lee S, et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy Clin Immunol. 2015. This article shows the positive effect of abatacept in CTLA4 haploinsuuficiency.
99.
Seidel MG et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. J Allergy Clin Immunol. 2015;135(5):1384–90 e1-8.CrossRefPubMedPubMedCentral
Metadata
Title
T Regulatory Cell Biology in Health and Disease
Authors
Fayhan J. Alroqi
Talal A. Chatila
Publication date
01-04-2016
Publisher
Springer US
Published in
Current Allergy and Asthma Reports / Issue 4/2016
Print ISSN: 1529-7322
Electronic ISSN: 1534-6315
DOI
https://doi.org/10.1007/s11882-016-0606-9

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