The goal of this study is to examine a novel hypothesis that the progression of diabetes is partially due to the weakened survival of CD25high T cells, and prolonging survival of CD25high T cells inhibits the development of diabetes. Since CD28 co-stimulation is essential for the survival of CD4+CD25high T cells, we determined whether CD28-upregulated translationally controlled tumor protein (TCTP) prolongs the survival of CD4+CD25high regulatory T cells (Tregs) by a transgenic approach. The TCTP transgene prevents Tregs from undergoing apoptosis induced by interleukin-2 withdrawal-, dexamethasone-, cyclophosphamide-, and anti-Fas treatment in vitro. In addition, transgenic Tregs express higher levels of FOXP3 than wild-type counterparts and maintain suppressive activity, suggesting that TCTP promotes Tregs escape from thymic negative selection, and that prolonged survival does not attenuate Treg suppression. Moreover, TCTP transgenic Tregs inhibit the development of autoimmune diabetes due to increased survival of suppressive Tregs and decreased expression of pancreatic TNF-α. Promoting the survival of CD25high T cells leads to prolonged survival of Tregs but not activated CD25+ non-Treg T cells. Thus, we propose a new model of “two phase survival” for Tregs. Our results suggest that modulation of Treg survival can be developed as a new therapy for autoimmune diseases.
Glisic-MilosavljevicSWaukauJJailwalaP. At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+ T-cell fraction. PLoS ONE2007; 2(1):e146.
2.
SalomonBLenschowDJRheeL. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity2000; 12:431–440.
3.
TaiXCowanMFeigenbaumL. CD28 costimulation of developing thymocytes induces FOXP3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol2005; 6:152–162.
4.
YanYChenYYangF. HLA-A2.1-restricted T cells react to SEREX-defined tumor antigen CML66L and are suppressed by CD4+CD25+ regulatory T cells. Int J Immunopathol Pharmacol2007; 20:75–89.
5.
YangYYangFXiongZ. An N-terminal region of translationally controlled tumor protein is required for its anti-apoptotic activity. Oncogene2005; 24:4778–4788.
6.
YangXF. Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets. Front Biosci2008; 13:1472–1499.
7.
LaiJHHorvathGSubleskiJ. RelA is a potent transcriptional activator of the CD28 response element within the interleukin 2 promoter. Mol Cell Biol1995; 15:4260–4271.
8.
XiongZSongJYanY. Higher expression of Bax in regulatory T cells increases vascular inflammation. Front Biosci2008; 13:7143–7155.
9.
ThorntonAMDonovanEEPiccirilloCA. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol2004; 172:6519–6523.
10.
YangXFWeberGFCantorH. A novel Bcl-x isoform connected to the T cell receptor regulates apoptosis in T cells. Immunity1997; 7:629–639.
11.
AnastasiECampeseAFBellaviaD. Expression of activated Notch3 in transgenic mice enhances generation of T regulatory cells and protects against experimental autoimmune diabetes. J Immunol2003; 171:4504–4511.
12.
KaneLPLinJWeissA. It's all Rel-ative: NF-kappaB and CD28 costimulation of T-cell activation. Trends Immunol2002; 23:413–420.
PiccaCCLarkinJ3rdBoesteanuA. Role of TCR specificity in CD4+ CD25+ regulatory T-cell selection. Immunol Rev2006; 212:74–85.
15.
de la RosaMRutzSDoraingerH. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol2004; 34:2480–2488.
16.
HeroldKCVezysVKoonsA. CD28/B7 costimulation regulates autoimmune diabetes induced with multiple low doses of streptozotocin. J Immunol1997; 158:984–991.
17.
IshikawaHOchiHChenML. Inhibition of autoimmune diabetes by oral administration of anti-CD3 monoclonal antibody. Diabetes2007; 56:2103–2109.
18.
HolstadMSandlerS. A transcriptional inhibitor of TNF-alpha prevents diabetes induced by multiple low-dose streptozotocin injections in mice. J Autoimmun2001; 16:441–447.
19.
MaierLMWickerLS. Genetic susceptibility to type 1 diabetes. Curr Opin Immunol2005; 17:601–608.
20.
SoldainiEPlaMBeermannF. Mouse interleukin-2 receptor alpha gene expression. Delimitation of cis-acting regulatory elements in transgenic mice and by mapping of DNase-I hypersensitive sites. J Biol Chem1995; 270:10733–10742.
21.
RoncadorGBrownPJMaestreL. Analysis of FOXP3 protein expression in human CD4(+)CD25(+) regulatory T cells at the single-cell level. Eur J Immunol2005; 35:1681–1691.
22.
MalekTRBayerAL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol2004; 4:665–674.
23.
ScheffoldAHuhnJHoferT. Regulation of CD4+CD25+ regulatory T cell activity: It takes (IL-)two to tango. Eur J Immunol2005; 35:1336–1341.
24.
KasprowiczDJDroinNSoperDM. Dynamic regulation of FOXP3 expression controls the balance between CD4(+) T cell activation and cell death. Eur J Immunol2005; 35:3424–3432.
25.
WangJIoan-FacsinayAvan der VoortEI. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol2007; 37:129–138.
26.
HeroldKCVezysVSunQ. Regulation of cytokine production during development of autoimmune diabetes induced with multiple low doses of streptozotocin. J Immunol1996; 156:3521–3527.
27.
BabayaNIkegamiHFujisawaT. Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11. Biochem Biophys Res Commun2005; 328:158–164.
28.
ValentijnAJGilmoreAP. Translocation of full-length Bid to mitochondria during anoikis. J Biol Chem2004; 279:32848–32857.
29.
TaamsLSSmithJRustinMH. Human anergic/suppressive CD4(+)CD25(+) T cells: A highly differentiated and apoptosis-prone population. Eur J Immunol2001; 31:1122–1131.
30.
ChenXMurakamiTOppenheimJJ. Differential response of murine CD4+CD25+ and CD4+CD25- T cells to dexamethasone-induced cell death. Eur J Immunol2004; 34:859–869.
31.
FritzschingBOberleNEberhardtN. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J Immunol2005; 175:32–36.
32.
GavinMARasmussenJPFontenotJD. Foxp3-dependent programme of regulatory T-cell differentiation. Nature2007; 445:771–775.
33.
BensingerSJBandeiraAJordanMS. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med2001; 194:427–438.
34.
BoiseLHMinnAJNoelPJ. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity1995; 3:87–98.
35.
D'CruzLMKleinL. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol2005; 6:1152–1159.
