At-Risk and Recent-Onset Type 1 Diabetic Subjects Have Increased Apoptosis in the CD4+CD25+high T-Cell Fraction

被引:56
作者
Glisic-Milosavljevic, Sanja [1 ,2 ,3 ]
Waukau, Jill [1 ,2 ,3 ]
Jailwala, Parthav [1 ,2 ,3 ]
Jana, Srikanta [1 ,2 ,3 ]
Khoo, Huoy-Jii [1 ,2 ,3 ]
Albertz, Hope [4 ]
Woodliff, Jeffrey [5 ]
Koppen, Marilyn [1 ,2 ,3 ]
Alemzadeh, Ramin [6 ]
Hagopian, William [7 ]
Ghosh, Soumitra [1 ,2 ,3 ]
机构
[1] Med Coll Wisconsin, Max McGee Natl Ctr Juvenile Diabet, Milwaukee, WI 53226 USA
[2] Med Coll Wisconsin, Human Mol Genet Ctr, Milwaukee, WI 53226 USA
[3] Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53201 USA
[4] Med Coll Wisconsin, Blood Ctr Wisconsin, Milwaukee, WI 53226 USA
[5] Med Coll Wisconsin, Dept Pediat, Flow Cytometry Core Facil, Milwaukee, WI 53226 USA
[6] Childrens Hosp Wisconsin, Med Coll Wisconsin, Diabet Ctr Pediat Endocrinol & Metab, Milwaukee, WI 53201 USA
[7] Pacific NW Res Inst, Seattle, WA USA
来源
PLOS ONE | 2007年 / 2卷 / 01期
基金
美国国家卫生研究院;
关键词
D O I
10.1371/journal.pone.0000146
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background. In experimental models, Type 1 diabetes (T1D) can be prevented by adoptive transfer of CD4+CD25+ (FoxP3+) suppressor or regulatory T cells. Recent studies have found a suppression defect of CD4+CD25+(high) T cells in human disease. In this study we measure apoptosis of CD4+CD25+(high) T cells to see if it could contribute to reduced suppressive activity of these cells. Methods and Findings. T-cell apoptosis was evaluated in children and adolescent (35 females/40 males) subjects comprising recent-onset and long-standing T1D subjects and their first-degree relatives, who are at variable risk to develop T1D. YOPRO1/7AAD and intracellular staining of the active form of caspase 3 were used to evaluate apoptosis. Isolated CD4+CD25+(high) and CD4+CD25- T cells were co-cultured in a suppression assay to assess the function of the former cells. We found that recent-onset T1D subjects show increased apoptosis of CD4+CD25+(high) T cells when compared to both control and long-standing T1D subjects (p<0.0001 for both groups). Subjects at high risk for developing T1D ( 2-3Ab+ve) show a similar trend (p<0.02 and p<0.01, respectively). On the contrary, in long-standing T1D and T2D subjects, CD4+CD25+(high) T cell apoptosis is at the same level as in control subjects (p = NS). Simultaneous intracellular staining of the active form of caspase 3 and FoxP3 confirmed recent-onset FoxP3+ve CD4+CD25+(high) T cells committed to apoptosis at a higher percentage (15.3 +/- 2.2) compared to FoxP3+ve CD4+CD25+(high) T cells in control subjects (6.1 +/- 1.7) (p<0.002). Compared to control subjects, both recent-onset T1D and high at-risk subjects had significantly decreased function of CD4+CD25+(high) T cells (p = 0.0007 and p = 0.007, respectively). Conclusions. There is a higher level of ongoing apoptosis in CD4+CD25+(high) T cells in recent-onset T1D subjects and in subjects at high risk for the disease. This high level of CD4+CD25+(high) T-cell apoptosis could be a contributing factor to markedly decreased suppressive potential of these cells in recent-onset T1D subjects.
引用
收藏
页数:7
相关论文
共 35 条
[1]   The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs [J].
Allan, SE ;
Passerini, L ;
Bacchetta, R ;
Crellin, N ;
Dai, MY ;
Orban, PC ;
Ziegler, SF ;
Roncarolo, MG ;
Levings, MK .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (11) :3276-3284
[2]   Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+CD25+ T cells [J].
Baecher-Allan, C ;
Wolf, E ;
Hafler, DA .
CLINICAL IMMUNOLOGY, 2005, 115 (01) :10-18
[3]   Inhibition of human CD4+CD25+high regulatory T cell function [J].
Baecher-Allan, C ;
Viglietta, V ;
Hafler, DA .
JOURNAL OF IMMUNOLOGY, 2002, 169 (11) :6210-6217
[4]   The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 [J].
Bennett, CL ;
Christie, J ;
Ramsdell, F ;
Brunkow, ME ;
Ferguson, PJ ;
Whitesell, L ;
Kelly, TE ;
Saulsbury, FT ;
Chance, PF ;
Ochs, HD .
NATURE GENETICS, 2001, 27 (01) :20-21
[5]   Functional defects and the influence of age on the frequency of CD4+CD25+ T-Cells in type 1 diabetes [J].
Brusko, TM ;
Wasserfall, CH ;
Clare-Salzler, MJ ;
Schatz, DA ;
Atkinson, MA .
DIABETES, 2005, 54 (05) :1407-1414
[6]   Regulating the immune system: the induction of regulatory T cells in the periphery [J].
Buckner, JH ;
Ziegler, SF .
ARTHRITIS RESEARCH & THERAPY, 2004, 6 (05) :215-222
[7]  
Dosch HM, 1999, J IMMUNOL, V163, P6933
[8]  
EISENBARTH GS, 1986, NEW ENGL J MED, V314, P1360
[9]   T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells [J].
Fahlén, L ;
Read, S ;
Gorelik, L ;
Hurst, SD ;
Coffman, RL ;
Flavell, RA ;
Powrie, F .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 201 (05) :737-746
[10]   High glucose causes apoptosis in cultured human pancreatic Islets of Langerhans - A potential role for regulation of specific Bcl family genes toward an apoptotic cell death program [J].
Federici, M ;
Hribal, M ;
Perego, L ;
Ranalli, M ;
Caradonna, Z ;
Perego, C ;
Usellini, L ;
Nano, R ;
Bonini, P ;
Bertuzzi, F ;
Marlier, LNJL ;
Davalli, AM ;
Carandente, O ;
Pontiroli, AE ;
Melino, G ;
Marchetti, P ;
Lauro, R ;
Sesti, G ;
Folli, F .
DIABETES, 2001, 50 (06) :1290-1301