T Cell Islet Accumulation in Type 1 Diabetes Is a Tightly Regulated, Cell-Autonomous Event

被引:116
作者
Lennon, Greig P. [1 ]
Bettini, Maria [1 ]
Burton, Amanda R. [1 ]
Vincent, Erica [1 ]
Arnold, Paula Y. [1 ]
Santamaria, Pere [2 ,3 ]
Vignali, Dario A. A. [1 ]
机构
[1] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA
[2] Univ Calgary, Julia McFarlane Diabet Res Ctr, Calgary, AB T2N 4N1, Canada
[3] Univ Calgary, Dept Microbiol & Infect Dis, Inst Inflammat Infect & Immun, Fac Med, Calgary, AB T2N 4N1, Canada
基金
加拿大健康研究院;
关键词
RECEPTOR RETROGENIC MICE; MHC CLASS-I; INSULITIS; PEPTIDE; CLONES; MOUSE; AUTOIMMUNITY; INFLAMMATION; RECRUITMENT; EXPRESSION;
D O I
10.1016/j.immuni.2009.07.008
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Type 1 diabetes is a T cell-mediated autoimmune disease, characterized by lymphocytic infiltration of the pancreatic islets. It is currently thought that islet antigen specificity is not a requirement for islet entry and that diabetogenic T cells can recruit a heterogeneous bystander T cell population. We tested this assumption directly by generating T cell receptor (TCR) retrogenic mice expressing two different T cell populations. By combining diabetogenic and nondiabetogenic or nonautoantigen-specific T cells, we demonstrate that by stander T cells cannot accumulate in the pancreatic islets. Autoantigen-specific T cells that accumulate in islets, but do not cause diabetes, were also unaffected by the presence of diabetogenic T cells. Additionally, 67% of TCRs cloned from nonobese diabetic (NOD) islet-infiltrating CD4(+) T cells were able to mediate cell-autonomous islet infiltration and/or diabetes when expressed in retrogenic mice. Therefore, islet entry and accumulation appears to be a cell-autonomous and tightly regulated event and is governed by islet antigen specificity.
引用
收藏
页码:643 / 653
页数:11
相关论文
共 31 条
[1]   Diabetes incidence is unaltered in glutamate decarboxylase 65-specific TCR retrogenic Nonobese diabetic mice: Generation by retroviral-mediated stem cell gene transfer [J].
Arnold, PY ;
Burton, AR ;
Vignali, DAA .
JOURNAL OF IMMUNOLOGY, 2004, 173 (05) :3103-3111
[2]   The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues [J].
Arnold, PY ;
La Gruta, NL ;
Miller, T ;
Vignali, KM ;
Adams, PS ;
Woodland, DL ;
Vignali, DAA .
JOURNAL OF IMMUNOLOGY, 2002, 169 (02) :739-749
[3]   Differential protection in two transgenic lines of NOD/Lt mice hyperexpressing the autoantigen GAD65 in pancreatic β-cells [J].
Bridgett, M ;
Cetkovic-Cvrlje, M ;
O'Rourke, R ;
Shi, YG ;
Narayanswami, S ;
Lambert, J ;
Ramiya, V ;
Baekkeskov, S ;
Leiter, EH .
DIABETES, 1998, 47 (12) :1848-1856
[4]   On the pathogenicity of autoantigen-specific T-cell receptors [J].
Burton, Amanda R. ;
Vincent, Erica ;
Arnold, Paula Y. ;
Lennon, Greig P. ;
Smeltzer, Matthew ;
Li, Chin-Shang ;
Haskins, Kathryn ;
Hutton, John ;
Tisch, Roland M. ;
Sercarz, Eli E. ;
Santamaria, Pere ;
Workman, Creg J. ;
Vignalil, Dario A. A. .
DIABETES, 2008, 57 (05) :1321-1330
[5]  
Cantagrel A, 1998, Int Rev Immunol, V17, P323, DOI 10.3109/08830189809054409
[6]   Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in nonobese diabetic mice [J].
Carvalho-Pinto, C ;
García, MI ;
Gómez, L ;
Ballesteros, A ;
Zaballos, A ;
Flores, JM ;
Mellado, M ;
Rodríguez-Frade, JM ;
Balomenos, D ;
Martinez, C .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2004, 34 (02) :548-557
[7]   Rapid identification of MHC class I-restricted antigens relevant to autoimmune diabetes using retrogenic T cells [J].
Chaparro, Rodolfo Jose ;
Burton, Amanda R. ;
Serreze, David V. ;
Vignali, Dario A. A. ;
DiLorenzo, Teresa P. .
JOURNAL OF IMMUNOLOGICAL METHODS, 2008, 335 (1-2) :106-115
[8]  
Christen U, 2004, J CLIN INVEST, V113, P74, DOI [10.1172/JCI17005, 10.1172/JCI200417005]
[9]   The nonobese diabetic mouse as a model of autoimmune diabetes: Immune dysregulation gets the NOD [J].
Delovitch, TL ;
Singh, B .
IMMUNITY, 1997, 7 (06) :727-738
[10]   Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor α chain gene rearrangement [J].
DiLorenzo, TP ;
Graser, RT ;
Ono, T ;
Christianson, GJ ;
Chapman, HD ;
Roopenian, DC ;
Nathenson, SG ;
Serreze, DV .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12538-12543