Abstract
CD4+CD25+ regulatory T cells (Tregs) are a class of CD4+ T cells with immunosuppressive functions that play a critical role in maintaining immune homeostasis. However, in certain disease settings, Tregs demonstrate plastic differentiation, and the stability of these Tregs, which is characterized by the stable expression or protective epigenetic modifications of the transcription factor Foxp3, becomes abnormal. Plastic Tregs have some features of helper T (Th) cells, such as the secretion of Th-related cytokines and the expression of specific transcription factors in Th cells, but also still retain the expression of Foxp3, a feature of Tregs. Although such Th-like Tregs can secrete pro-inflammatory cytokines, they still possess a strong ability to inhibit specific Th cell responses. Therefore, the plastic differentiation of Tregs not only increases the complexity of the immune circumstances under pathological conditions, especially autoimmune diseases, but also shows an association with changes in the stability of Tregs. The plastic differentiation and stability change of Tregs play vital roles in the progression of diseases. This review focuses on the phenotypic characteristics, functions, and formation conditions of several plastic Tregs and also summarizes the changes of Treg stability and their effects on inhibitory function. Additionally, the effects of Treg plasticity and stability on disease prognosis for several autoimmune diseases were also investigated in order to better understand the relationship between Tregs and autoimmune diseases.
Similar content being viewed by others
References
Lee YH, Bae SC (2017) Association between functional CYP2D6 polymorphisms and susceptibility to autoimmune diseases: a meta-analysis. Immunol Investig 46(2):109–122
Ortona E et al (2016) Sex-based differences in autoimmune diseases. Ann Ist Super Sanita 52(2):205–212
Marrack P, Kappler J, Kotzin BL (2001) Autoimmune disease: why and where it occurs. Nat Med 7(8):899–905
Becker KG (2004) The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 62(2):309–317
Tan Y et al (2016) CD24: from a hematopoietic differentiation antigen to a genetic risk factor for multiple autoimmune diseases. Clin Rev Allergy Immunol 50(1):70–83
Gravano DM, Hoyer KK (2013) Promotion and prevention of autoimmune disease by CD8+ T cells. J Autoimmun 45:68–79
Lee YH, Bae SC (2016) Association between interferon-gamma +874 T/a polymorphism and susceptibility to autoimmune diseases: a meta-analysis. Lupus 25(7):710–718
Walecki M et al (2015) Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells. Mol Biol Cell 26(15):2845–2857
Hwangbo C et al (2016) Syntenin regulates TGF-beta1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-beta type I receptor internalization. Oncogene 35(3):389–401
Dardalhon V et al (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat Immunol 9(12):1347–1355
Li F et al (2015) Insufficient secretion of IL-10 by Tregs compromised its control on over-activated CD4+ T effector cells in newly diagnosed adult immune thrombocytopenia patients. Immunol Res 61(3):269–280
Subramanian M et al (2013) Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest 123(1):179–188
Bommireddy R et al (2003) TGF beta 1 inhibits Ca2+−calcineurin-mediated activation in thymocytes. J Immunol 170(7):3645–3652
Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26(5):579–591
Zhang D et al (2015) Manipulating regulatory T cells: a promising strategy to treat autoimmunity. Immunotherapy 7(11):1201–1211
Yang WY et al (2015) Pathological conditions re-shape physiological Tregs into pathological Tregs. Burns Trauma 3(1)
Jager A et al (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183(11):7169–7177
Lohning M et al (2008) Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. J Exp Med 205(1):53–61
Bending D et al (2009) Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 119(3):565–572
Harbour SN et al (2015) Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 112(22):7061–7066
Lee YK et al (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30(1):92–107
Arterbery AS et al (2016) Production of proinflammatory cytokines by monocytes in liver-transplanted recipients with de novo autoimmune hepatitis is enhanced and induces TH1-like regulatory T cells. J Immunol 196(10):4040–4051
Xu X et al (2017) IFN-gamma-producing Th1-like regulatory T cells may limit acute cellular renal allograft rejection: paradoxical post-transplantation effects of IFN-gamma. Immunobiology 222(2):280–290
Zheng J et al (2011) Generation of human Th1-like regulatory CD4+ T cells by an intrinsic IFN-gamma- and T-bet-dependent pathway. Eur J Immunol 41(1):128–139
Li Y et al (2016) USP21 prevents the generation of T-helper-1-like Treg cells. Nat Commun 7:13559
Colbeck EJ et al (2015) Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors. Oncotarget 6(28):24649–24659
Huang CH et al (2017) Oral administration with diosgenin enhances the induction of intestinal T helper 1-like regulatory T cells in a murine model of food allergy. Int Immunopharmacol 42:59–66
Araya N et al (2014) HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells. J Clin Invest 124(8):3431–3442
Koch MA et al (2012) T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 37(3):501–510
Lee JH et al (2015) E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1alpha to maintain regulatory T cell stability and suppressive capacity. Immunity 42(6):1062–1074
Levine AG et al (2017) Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546(7658):421–425
Venigalla RK et al (2012) Identification of a human Th1-like IFNgamma-secreting Treg subtype deriving from effector T cells. J Autoimmun 39(4):377–387
Yamada A et al (2015) Impaired expansion of regulatory T cells in a neonatal thymectomy-induced autoimmune mouse model. Am J Pathol 185(11):2886–2897
Hall BM et al (2015) Induction of antigen specific CD4(+)CD25(+)Foxp3(+)T regulatory cells from naive natural thymic derived T regulatory cells. Int Immunopharmacol 28(2):875–886
Piconese S et al (2014) Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. Hepatology 60(5):1494–1507
Piconese S, Timperi E, Barnaba V (2014) Hardcore' OX40+ immunosuppressive regulatory T cells in hepatic cirrhosis and cancer. Oncoimmunology 3:e29257
Dominguez-Villar M, Baecher-Allan CM, Hafler DA (2011) Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med 17(6):673–675
McClymont SA et al (2011) Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 186(7):3918–3926
Hall AO et al (2012) The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37(3):511–523
Wang Y et al (2010) An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo. J Immunol 185(10):5983–5992
Li L et al (2016) Block of both TGF-beta and IL-2 signaling impedes Neurophilin-1+ regulatory T cell and follicular regulatory T cell development. Cell Death Dis 7(10):e2439
Daniel V, Trojan K, Opelz G (2016) Immunosuppressive drugs affect induction of IFNy+ Treg in vitro. Hum Immunol 77(1):146–152
Noval RM et al (2015) Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42(3):512–523
Hall BM et al (2013) Do natural T regulatory cells become activated to antigen specific T regulatory cells in transplantation and in autoimmunity? Front Immunol 4:208
Massoud AH et al (2016) An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med 22(9):1013–1022
Fujino M, Li XK (2013) Role of STAT3 in regulatory T lymphocyte plasticity during acute graft-vs.-host-disease. JAKSTAT 2(4):e24529
Wang Y, Su MA, Wan YY (2011) An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35(3):337–348
Afzali B et al (2010) Translational mini-review series on Th17 cells: induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 159(2):120–130
Tarique M et al (2017) IL-12 and IL-23 modulate plasticity of FoxP3+ regulatory T cells in human Leprosy. Mol Immunol 83:72–81
Coomes SM, Pelly VS, Wilson MS (2013) Plasticity within the alphabeta(+)CD4(+) T-cell lineage: when, how and what for? Open Biol 3(1):120157
Lee W et al (2016) Transcription factor IRF8 controls Th1-like regulatory T-cell function. Cell Mol Immunol 13(6):785–794
Nosko A et al (2017) T-bet enhances regulatory T cell fitness and directs control of Th1 responses in crescentic GN. J Am Soc Nephrol 28(1):185–196
Verma ND et al (2014) Interleukin-12 (IL-12p70) promotes induction of highly potent Th1-Like CD4(+)CD25(+) T regulatory cells that inhibit allograft rejection in unmodified recipients. Front Immunol 5:190
Jin HS et al (2013) Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest 123(11):4923–4934
MacDonald KG et al (2015) Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J Allergy Clin Immunol 135(4):946–955
Moosbrugger-Martinz V et al (2016) Atopic dermatitis induces the expansion of thymus-derived regulatory T cells exhibiting a Th2-like phenotype in mice. J Cell Mol Med 20(5):930–938
Zheng Y et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458(7236):351–356
Sawant DV, Vignali DA (2014) Once a Treg, always a Treg? Immunol Rev 259(1):173–191
Wohlfert EA et al (2011) GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 121(11):4503–4515
Malard F et al (2014) Increased Th17/Treg ratio in chronic liver GVHD. Bone Marrow Transplant 49(4):539–544
Zhang C et al (2014) The alteration of Th1/Th2/Th17/Treg paradigm in patients with type 2 diabetes mellitus: Relationship with diabetic nephropathy. Hum Immunol 75(4):289–296
Voo KS et al (2009) Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A 106(12):4793–4798
Kleinewietfeld M, Hafler DA (2013) The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol 25(4):305–312
Cho SN et al (2014) Role of staphylococcal enterotoxin B on the differentiation of regulatory T cells in nasal polyposis. Am J Rhinol Allergy 28(1):e17–e24
Chellappa S et al (2016) Regulatory T cells that co-express RORgammat and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer. Oncoimmunology 5(4):e1102828
Lochner M et al (2008) In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med 205(6):1381–1393
Sefik E et al (2015) Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 349(6251):993–997
Kitamura K, Farber JM, Kelsall BL (2010) CCR6 marks regulatory T cells as a colon-tropic, IL-10-producing phenotype. J Immunol 185(6):3295–3304
Villares R et al (2009) CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues. Eur J Immunol 39(6):1671–1681
Kluger MA et al (2014) Stat3 programs Th17-specific regulatory T cells to control GN. J Am Soc Nephrol 25(6):1291–1302
Zhou L et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240
Beriou G et al (2009) IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113(18):4240–4249
Krebs CF, Steinmetz OM (2016) CD4+ T cell fate in glomerulonephritis: a tale of Th1, Th17, and novel treg subtypes. Mediat Inflamm 2016:5393894
Turner JE et al (2010) CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis. J Am Soc Nephrol 21(6):974–985
Kluger MA et al (2016) Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus. Kidney Int 89(1):158–166
King C (2009) New insights into the differentiation and function of T follicular helper cells. Nat Rev Immunol 9(11):757–766
Maceiras AR et al (2017) T follicular helper and T follicular regulatory cells have different TCR specificity. Nat Commun 8:15067
Linterman MA et al (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17(8):975–982
Chung Y et al (2011) Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 17(8):983–988
Chowdhury A et al (2015) Decreased T follicular regulatory cell/T follicular helper cell (TFH) in simian immunodeficiency virus-infected rhesus macaques may contribute to accumulation of TFH in chronic infection. J Immunol 195(7):3237–3247
Zhou Q et al (2015) Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis 74(6):1265–1274
Nie J et al (2015) FOXP3(+) Treg cells and gender bias in autoimmune diseases. Front Immunol 6:493
Chapman NM, Chi H (2014) mTOR signaling, Tregs and immune modulation. Immunotherapy 6(12):1295–1311
Li X, Zheng Y (2015) Regulatory T cell identity: formation and maintenance. Trends Immunol 36(6):344–353
Ellis SD et al (2014) Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor alpha and CD86. Arthritis Rheumatol 66(10):2694–2705
Chakraborty S et al (2017) Transcriptional regulation of FOXP3 requires integrated activation of both promoter and CNS regions in tumor-induced CD8+ Treg cells. Sci Rep 7(1):1628
Park MK et al (2016) Amelioration of autoimmune arthritis by adoptive transfer of Foxp3-expressing regulatory B cells is associated with the Treg/Th17 cell balance. J Transl Med 14(1):191
Melis D et al (2017) Cutting edge: increased autoimmunity risk in glycogen storage disease type 1b is associated with a reduced engagement of glycolysis in T cells and an impaired regulatory T cell function. J Immunol 198(10):3803–3808
Prins JR et al (2015) Unstable Foxp3+ regulatory T cells and altered dendritic cells are associated with lipopolysaccharide-induced fetal loss in pregnant interleukin 10-deficient mice. Biol Reprod 93(4):95
Rossetti M et al (2017) TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis. Ann Rheum Dis 76(2):435–441
Alvarez SE et al (2017) Methylation of FOXP3 TSDR underlies the impaired suppressive function of Tregs from long-term belatacept-treated kidney transplant patients. Front Immunol 8:219
Paparo L et al (2016) Epigenetic features of FoxP3 in children with cow’s milk allergy. Clin Epigenetics 8:86
Wang L et al (2013) Mbd2 promotes foxp3 demethylation and T-regulatory-cell function. Mol Cell Biol 33(20):4106–4115
Gu J et al (2017) Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions. Cell Mol Immunol 14(6):521–528
Arroyo HR et al (2017) CD45RA distinguishes CD4+CD25+CD127−/low TSDR demethylated regulatory t cell subpopulations with differential stability and susceptibility to tacrolimus-mediated inhibition of suppression. Transplantation 101(2):302–309
He X et al (2017) Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci Rep 7:43003
Bailey-Bucktrout SL et al (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39(5):949–962
Nair VS, Oh KI (2014) Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells. Biochem Biophys Res Commun 450(1):918–924
Miyao T et al (2012) Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36(2):262–275
Huss DJ et al (2015) In vivo maintenance of human regulatory T cells during CD25 blockade. J Immunol 194(1):84–92
Kumar S et al (2013) CD4+CD25+ T regs with acetylated FoxP3 are associated with immune suppression in human leprosy. Mol Immunol 56(4):513–520
Song X et al (2012) Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function. Cell Rep 1(6):665–675
Wang L et al (2016) Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3+ T-regulatory cell function and promotes antitumor immunity. EBioMedicine 13:99–112
Xiao Y et al (2014) Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep 7(5):1471–1480
Du T et al (2013) Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers. Exp Mol Pathol 95(1):38–45
Li J et al (2015) Mammalian sterile 20-like kinase 1 (Mst1) enhances the stability of forkhead box P3 (Foxp3) and the function of regulatory t cells by modulating Foxp3 acetylation. J Biol Chem 290(52):30762–30770
Beier UH et al (2012) Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci Signal 5(229):ra45
Du X et al (2014) Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease. J Immunol 192(4):1525–1535
Kumar S et al (2017) Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation. J Leukoc Biol 101(2):429–438
Geng J et al (2017) The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells. Nat Immunol 18(7):800–812
Li C et al (2014) MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation. Proc Natl Acad Sci U S A 111(27):E2807–E2816
Wu C et al (2014) Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity 41(2):270–282
Harb H et al (2015) Childhood allergic asthma is associated with increased IL-13 and FOXP3 histone acetylation. J Allergy Clin Immunol 136(1):200–202
Deng G et al (2015) Pim-2 kinase influences regulatory T cell function and stability by mediating Foxp3 protein N-terminal phosphorylation. J Biol Chem 290(33):20211–20220
Morawski PA et al (2013) Foxp3 protein stability is regulated by cyclin-dependent kinase 2. J Biol Chem 288(34):24494–24502
Zhang Y et al (2016) Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells. Hum Vaccin Immunother 12(10):2512–2518
Zhuo C et al (2014) Higher FOXP3-TSDR demethylation rates in adjacent normal tissues in patients with colon cancer were associated with worse survival. Mol Cancer 13:153
Okada M et al (2014) Regulation of regulatory T cells: epigenetics and plasticity. Adv Immunol 124:249–273
Huehn J, Beyer M (2015) Epigenetic and transcriptional control of Foxp3+ regulatory T cells. Semin Immunol 27(1):10–18
Bending D et al (2014) Hypomethylation at the regulatory T cell-specific demethylated region in CD25hi T cells is decoupled from FOXP3 expression at the inflamed site in childhood arthritis. J Immunol 193(6):2699–2708
Jiao J et al (2017) Proximity ligation assay to quantify Foxp3 acetylation in regulatory T cells. Methods Mol Biol 1510:287–293
Liu Y et al (2014) Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function. Mol Cell Biol 34(21):3993–4007
Hori S (2014) Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells. Immunol Rev 259(1):159–172
Duarte JH et al (2009) Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 39(4):948–955
Bruce DL et al (2012) Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-beta pathway. Cell Signal 24(11):1999–2006
Takimoto T et al (2010) Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. J Immunol 185(2):842–855
Verrecchia F et al (2001) Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner. Oncogene 20(26):3332–3340
Jiang R et al (2017) The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion. Nat Commun 8:15129
Barsheshet Y et al (2017) CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A 114(23):6086–6091
van der Touw W et al (2013) Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol 190(12):5921–5925
Rauch KS et al (2016) Id3 maintains Foxp3 expression in regulatory T cells by controlling a transcriptional network of E47, Spi-B, and SOCS3. Cell Rep 17(11):2827–2836
Hsiao HW et al (2015) Deltex1 antagonizes HIF-1alpha and sustains the stability of regulatory T cells in vivo. Nat Commun 6:6353
Takahashi R et al (2011) SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med 208(10):2055–2067
Zhang P et al (2013) PARP-1 controls immunosuppressive function of regulatory T cells by destabilizing Foxp3. PLoS One 8(8):e71590
Singh K et al (2014) Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant 14(12):2691–2703
Cheng LS et al (2017) HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection. Clin Sci (Lond) 131(5):381–394
Zwang NA et al (2016) Selective sparing of human Tregs by pharmacologic inhibitors of the phosphatidylinositol 3-kinase and MEK pathways. Am J Transplant 16(9):2624–2638
Han JM, Patterson SJ, Levings MK (2012) The role of the PI3K signaling pathway in CD4(+) T cell differentiation and function. Front Immunol 3:245
Huynh A et al (2015) Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16(2):188–196
Shrestha S et al (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16(2):178–187
Delgoffe GM et al (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256
Yadav M et al (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209(10):1713–1722 S1–19
Weiss JM et al (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209(10):1723–1742 S1
Jeker LT et al (2013) DGCR8-mediated production of canonical microRNAs is critical for regulatory T cell function and stability. PLoS One 8(5):e66282
Revilla-Nuin B et al (2017) Differential profile of activated regulatory T cell subsets and microRNAs in tolerant liver transplant recipients. Liver Transpl 23(7):933–945
Zhou X et al (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10(9):1000–1007
Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8(3):277–284
Oldenhove G et al (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31(5):772–786
Schaer DA et al (2013) GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol Res 1(5):320–331
Overacre-Delgoffe AE et al (2017) Interferon-gamma drives Treg fragility to promote anti-tumor immunity. Cell 169(6):1130–1141.e11
Sawant DV et al (2015) The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways. Immunology 145(1):11–23
Layman A et al (2017) Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease. Nat Commun 8:15677
Belle L et al (2016) Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression. Blood 128(16):2068–2082
Knosp CA et al (2013) Regulation of Foxp3+ inducible regulatory T cell stability by SOCS2. J Immunol 190(7):3235–3245
Butcher MJ et al (2016) Atherosclerosis-driven Treg plasticity results in formation of a dysfunctional subset of plastic IFNgamma+ Th1/Tregs. Circ Res 119(11):1190–1203
Trojan K et al (2017) Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function. PLoS One 12(3):e0173773
Yang BH et al (2016) Foxp3(+) T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 9(2):444–457
Trojan K et al (2016) IFNy+ and IFNy- Treg subsets with stable and unstable Foxp3 expression in kidney transplant recipients with good long-term graft function. Transpl Immunol
Daniel V et al (2015) IFNgamma+ Treg in-vivo and in-vitro represent both activated nTreg and peripherally induced aTreg and remain phenotypically stable in-vitro after removal of the stimulus. BMC Immunol 16:45
Alpdogan O, van den Brink MR (2012) Immune tolerance and transplantation. Semin Oncol 39(6):629–642
Zeng H et al (2015) Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol Immunol 12(5):566–571
van Delft MA, Huitema LF, Tas SW (2015) The contribution of NF-kappaB signalling to immune regulation and tolerance. Eur J Clin Investig 45(5):529–539
La Rocca C et al (2014) The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett 162(1 Pt A):41–48
Herkel J (2015) Regulatory T cells in hepatic immune tolerance and autoimmune liver diseases. Dig Dis 33(Suppl 2):70–74
Cortes JR et al (2014) Maintenance of immune tolerance by Foxp3+ regulatory T cells requires CD69 expression. J Autoimmun 55:51–62
Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27:313–338
Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11(1):7–13
Cvetanovich GL, Hafler DA (2010) Human regulatory T cells in autoimmune diseases. Curr Opin Immunol 22(6):753–760
Komatsu N et al (2014) Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 20(1):62–68
Schinnerling K et al (2017) The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis. Clin Exp Immunol 189(1):12–20
Wang T et al (2015) Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood. Ann Rheum Dis 74(6):1293–1301
Xia M et al (2017) Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity. Nat Commun 8:15818
Nie H et al (2013) Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med 19(3):322–328
Rossetti M et al (2015) Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region. J Immunol 194(1):113–124
Muto G et al (2013) TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity. PLoS One 8(9):e74639
Jamshidian A et al (2013) Biased Treg/Th17 balance away from regulatory toward inflammatory phenotype in relapsed multiple sclerosis and its correlation with severity of symptoms. J Neuroimmunol 262(1–2):106–112
AP J et al (2017) Altered regulatory T-cell fractions and Helios expression in clinically isolated syndrome:clues to the development of multiple sclerosis. Clin Transl Immunol 6(5):e143
Nyirenda MH et al (2015) TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis. J Immunol 194(12):5761–5774
Rakebrandt N, Littringer K, Joller N (2016) Regulatory T cells: balancing protection versus pathology. Swiss Med Wkly 146:w14343
Kitz A et al (2016) AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep 17(8):1169–1183
O'Connor RA et al (2010) Myelin-reactive, TGF-beta-induced regulatory T cells can be programmed to develop Th1-like effector function but remain less proinflammatory than myelin-reactive Th1 effectors and can suppress pathogenic T cell clonal expansion in vivo. J Immunol 185(12):7235–7243
Cerosaletti K et al (2013) Multiple autoimmune-associated variants confer decreased IL-2R signaling in CD4+ CD25(hi) T cells of type 1 diabetic and multiple sclerosis patients. PLoS One 8(12):e83811
Fletcher JM et al (2009) CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 183(11):7602–7610
Muls NG et al (2015) Regulation of Treg-associated CD39 in multiple sclerosis and effects of corticotherapy during relapse. Mult Scler 21(12):1533–1545
Esposito M et al (2010) IL-17- and IFN-gamma-secreting Foxp3+ T cells infiltrate the target tissue in experimental autoimmunity. J Immunol 185(12):7467–7473
Li X et al (2014) Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158(4):734–748
Du W et al (2013) Foxp3+ Treg expanded from patients with established diabetes reduce Helios expression while retaining normal function compared to healthy individuals. PLoS One 8(2):e56209
Graves CL et al (2016) Intestinal epithelial cell regulation of adaptive immune dysfunction in human type 1 diabetes. Front Immunol 7:679
Tan TG, Mathis D, Benoist C (2016) Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proc Natl Acad Sci U S A 113(49):14103–14108
Kornete M, Sgouroudis E, Piccirillo CA (2012) ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J Immunol 188(3):1064–1074
Marwaha AK et al (2010) Cutting edge: increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J Immunol 185(7):3814–3818
Kumar P, Subramaniyam G (2015) Molecular underpinnings of Th17 immune-regulation and their implications in autoimmune diabetes. Cytokine 71(2):366–376
Visperas A, Vignali DA (2016) Are regulatory T cells defective in type 1 diabetes and can we fix them? J Immunol 197(10):3762–3770
Ferreira RC et al (2017) Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity. J Autoimmun 84:75–86
D'Hennezel E, Kornete M, Piccirillo CA (2010) IL-2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease. J Transl Med 8:113
Jeker LT et al (2012) MicroRNA 10a marks regulatory T cells. PLoS One 7(5):e36684
Bovenschen HJ et al (2011) Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol 131(9):1853–1860
Gatzka M, Scharffetter-Kochanek K (2015) T-cell plasticity in inflammatory skin diseases--the good, the bad, and the chameleons. J Dtsch Dermatol Ges 13(7):647–652
Fiocco U et al (2015) Transcriptional network profile on synovial fluid T cells in psoriatic arthritis. Clin Rheumatol 34(9):1571–1580
Yang L et al (2016) Impaired function of regulatory T cells in patients with psoriasis is mediated by phosphorylation of STAT3. J Dermatol Sci 81(2):85–92
Singh K et al (2013) Reduced CD18 levels drive regulatory T cell conversion into Th17 cells in the CD18hypo PL/J mouse model of psoriasis. J Immunol 190(6):2544–2553
Soler DC, McCormick TS (2011) The dark side of regulatory T cells in psoriasis. J Invest Dermatol 131(9):1785–1786
He X et al (2014) Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production. J Invest Dermatol 134(4):975–983
Soler DC et al (2013) Psoriasis patients exhibit impairment of the high potency CCR5(+) T regulatory cell subset. Clin Immunol 149(1):111–118
Zhang HY et al (2015) Target tissue ectoenzyme CD39/CD73-expressing Foxp3+ regulatory T cells in patients with psoriasis. Clin Exp Dermatol 40(2):182–191
Liu X et al (2013) Elevated levels of CD4(+)CD25(+)FoxP3(+) T cells in systemic sclerosis patients contribute to the secretion of IL-17 and immunosuppression dysfunction. PLoS One 8(6):e64531
Almanzar G et al (2016) Disease manifestation and inflammatory activity as modulators of Th17/Treg balance and RORC/FoxP3 methylation in systemic sclerosis. Int Arch Allergy Immunol 171(2):141–154
Wang YY et al (2014) DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. Br J Dermatol 171(1):39–47
Alexander T et al (2013) Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis 72(9):1549–1558
Katsuyama E et al (2017) Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells. J Immunol 198(11):4268–4276
Frank-Bertoncelj M, Gay S (2014) The epigenome of synovial fibroblasts: an underestimated therapeutic target in rheumatoid arthritis. Arthritis Res Ther 16(3):117
Park JS et al (2014) STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis Rheumatol 66(4):918–929
Caplazi P et al (2015) Mouse models of rheumatoid arthritis. Vet Pathol 52(5):819–826
Cooles FA, Isaacs JD, Anderson AE (2013) Treg cells in rheumatoid arthritis: an update. Curr Rheumatol Rep 15(9):352
Shalini PU et al (2015) A study on FoxP3 and Tregs in paired samples of peripheral blood and synovium in rheumatoid arthritis. Cent Eur J Immunol 40(4):431–436
Alunno A et al (2015) Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediat Inflamm 2015:751793
Noack M, Miossec P (2014) Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13(6):668–677
Jimeno R et al (2015) Th17 polarization of memory Th cells in early arthritis: the vasoactive intestinal peptide effect. J Leukoc Biol 98(2):257–269
Li N et al (2015) The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis. Int J Clin Exp Med 8(9):15043–15053
Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15(9):545–558
Bhargava P, Mowry EM (2014) Gut microbiome and multiple sclerosis. Curr Neurol Neurosci Rep 14(10):492
Karussis D (2014) The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review. J Autoimmun 48-49:134–142
Noori-Zadeh A et al (2016) Regulatory T cell number in multiple sclerosis patients: a meta-analysis. Mult Scler Relat Disord 5:73–76
Pennisi M et al (2013) Agent based modeling of Treg-Teff cross regulation in relapsing-remitting multiple sclerosis. BMC Bioinf 14(Suppl 16):S9
Etesam Z et al (2016) Altered expression of specific transcription factors of Th17 (RORgammat, RORalpha) and Treg lymphocytes (FOXP3) by peripheral blood mononuclear cells from patients with multiple sclerosis. J Mol Neurosci 60(1):94–101
Naghavian R et al (2015) miR-141 and miR-200a, revelation of new possible players in modulation of Th17/Treg differentiation and pathogenesis of multiple sclerosis. PLoS One 10(5):e0124555
McPherson RC et al (2015) T-bet expression by Foxp3(+) T regulatory cells is not essential for their suppressive function in CNS autoimmune disease or colitis. Front Immunol 6:69
Gao Y et al (2015) Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc Natl Acad Sci U S A 112(25):E3246–E3254
Segal BM (2012) The unwavering commitment of regulatory T cells in the suppression of autoimmune encephalomyelitis: another aspect of immune privilege in the CNS. Eur J Immunol 42(5):1102–1105
O'Connor RA et al (2012) Foxp3(+) Treg cells in the inflamed CNS are insensitive to IL-6-driven IL-17 production. Eur J Immunol 42(5):1174–1179
Xie Z, Chang C, Zhou Z (2014) Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol 47(2):174–192
Simmons K, Michels AW (2014) Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease. Rheum Dis Clin N Am 40(4):797–811
ElEssawy B, Li XC (2015) Type 1 diabetes and T regulatory cells. Pharmacol Res 98:22–30
Serr I et al (2014) Treg vaccination in autoimmune type 1 diabetes. BioDrugs 28(1):7–16
Bluestone JA et al (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7(315):315ra189
Kornete M et al (2015) Th1-Like ICOS+ Foxp3+ Treg cells preferentially express CXCR3 and home to beta-islets during pre-diabetes in BDC2.5 NOD Mice. PLoS One 10(5):e0126311
Jiang S, Hinchliffe TE, Wu T (2015) Biomarkers of an autoimmune skin disease—psoriasis. Genomics Proteomics Bioinformatics 13(4):224–233
Boehncke WH, Schon MP (2015) Psoriasis. Lancet 386(9997):983–994
Elhai M et al (2015) Systemic sclerosis: recent insights. Joint Bone Spine 82(3):148–153
Stern EP, Denton CP (2015) The pathogenesis of systemic sclerosis. Rheum Dis Clin N Am 41(3):367–382
Oka T et al (2017) CXCL17 attenuates imiquimod-induced psoriasis-like skin inflammation by recruiting myeloid-derived suppressor cells and regulatory T cells. J Immunol 198(10):3897–3908
Kataoka H et al (2015) Decreased expression of Runx1 and lowered proportion of Foxp3(+) CD25(+) CD4(+) regulatory T cells in systemic sclerosis. Mod Rheumatol 25(1):90–95
Mattozzi C et al (2013) Importance of regulatory T cells in the pathogenesis of psoriasis: review of the literature. Dermatology 227(2):134–145
Papp G et al (2012) The effects of extracorporeal photochemotherapy on T cell activation and regulatory mechanisms in patients with systemic sclerosis. Clin Rheumatol 31(9):1293–1299
Cripps JG et al (2012) Liver inflammation in a mouse model of Th1 hepatitis despite the absence of invariant NKT cells or the Th1 chemokine receptors CXCR3 and CCR5. Lab Invest 92(10):1461–1471
Kim SM et al (2014) 27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes. Toxicol Appl Pharmacol 274(3):462–470
Chen L et al (2013) mTORC2-PKBalpha/Akt1 Serine 473 phosphorylation axis is essential for regulation of FOXP3 Stability by chemokine CCL3 in psoriasis. J Invest Dermatol 133(2):418–428
Komai-Koma M et al (2007) IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol 37(10):2779–2786
Yu C, Gershwin ME, Chang C (2014) Diagnostic criteria for systemic lupus erythematosus: a critical review. J Autoimmun 48-49:10–13
Mohan C, Putterman C (2015) Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol 11(6):329–341
Ohl K, Tenbrock K (2015) Regulatory T cells in systemic lupus erythematosus. Eur J Immunol 45(2):344–355
Golding A et al (2013) The percentage of FoxP3+Helios+ Treg cells correlates positively with disease activity in systemic lupus erythematosus. Arthritis Rheum 65(11):2898–2906
Kaser T et al (2015) Natural and inducible Tregs in swine: helios expression and functional properties. Dev Comp Immunol 49(2):323–331
Larkin JR et al (2013) Regulation of interferon gamma signaling by suppressors of cytokine signaling and regulatory T cells. Front Immunol 4:469
Taleb S, Tedgui A, Mallat Z (2015) IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles. Arterioscler Thromb Vasc Biol 35(2):258–264
Melzer S et al (2015) Nanoparticle uptake by macrophages in vulnerable plaques for atherosclerosis diagnosis. J Biophotonics 8(11–12):871–883
Matsuura E et al (2014) Is atherosclerosis an autoimmune disease? BMC Med 12:47
Hasib L et al (2016) Functional and homeostatic defects of regulatory T cells in patients with coronary artery disease. J Intern Med 279(1):63–77
Cosmi L et al (2014) Th17 plasticity: pathophysiology and treatment of chronic inflammatory disorders. Curr Opin Pharmacol 17:12–16
Ueno A et al (2015) Th17 plasticity and its changes associated with inflammatory bowel disease. World J Gastroenterol 21(43):12283–12295
Chen Y et al (2017) IFN-gamma-expressing Th17 cells are required for development of severe ocular surface autoimmunity. J Immunol 199(3):1163–1169
Acknowledgments
We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81573929, 81373232, 81673937, 81703815), Jiangsu Provincial Natural Science Foundation of China (Grant No. BK2012458), and Priority Academic Program Development of Jiangsu Higher Education Institutions.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Qiu, R., Zhou, L., Ma, Y. et al. Regulatory T Cell Plasticity and Stability and Autoimmune Diseases. Clinic Rev Allerg Immunol 58, 52–70 (2020). https://doi.org/10.1007/s12016-018-8721-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12016-018-8721-0