Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion

被引：402

作者：

Delong, Thomas ^{[1
]}

Wiles, Timothy A. ^{[1
]}

Baker, Rocky L. ^{[1
]}

Bradley, Brenda ^{[1
]}

Barbour, Gene ^{[1
]}

Reisdorph, Richard ^{[2
]}

Armstrong, Michael ^{[2
]}

Powell, Roger L. ^{[2
]}

Reisdorph, Nichole ^{[2
]}

Kumar, Nitesh ^{[3
]}

Elso, Colleen M. ^{[3
]}

DeNicola, Megan ^{[4
]}

Bottino, Rita ^{[5
]}

Powers, Alvin C. ^{[6
,7
,8
]}

Harlan, David M. ^{[4
]}

Kent, Sally C. ^{[4
]}

Mannering, Stuart I. ^{[3
,9
]}

Haskins, Kathryn ^{[1
]}

机构：

[1] Univ Colorado, Sch Med, Dept Immunol & Microbiol, Anschutz Med Campus, Aurora, CO 80045 USA

[2] Univ Colorado, Sch Med, Pharmaceut Sci, Aurora, CO 80045 USA

[3] St Vincents Inst Med Res, Immunol & Diabet Unit, 9 Princes St, Fitzroy, Vic 3065, Australia

[4] Univ Massachusetts, Sch Med, Dept Med, Diabet Div,Diabet Ctr Excellence, Worcester, MA USA

[5] Allegheny Hlth Network, Inst Cellular Therapeut, Allegheny Singer Res Inst, Pittsburgh, PA USA

[6] Vanderbilt Univ, Med Ctr, Dept Med, Div Diabet Endocrinol & Metab, Nashville, TN USA

[7] Vanderbilt Univ, Dept Mol Physiol & Biophys, Med Ctr, Nashville, TN 37232 USA

[8] VA Tennessee Valley Healthcare Syst, Nashville, TN USA

[9] Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic 3065, Australia

来源：

SCIENCE | 2016年 / 351卷 / 6274期

基金：

英国医学研究理事会;

关键词：

CHROMOGRANIN-A; ANTIGEN; HLA-DQ8; CLONES;

D O I：

10.1126/science.aad2791

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：

T cell-mediated destruction of insulin-producing beta cells in the pancreas causes type 1 diabetes T1D). CD4 T cell responses play a central role in beta cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in beta cell secretory granules. These hybrid insulin peptides HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in beta cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.

引用

页码：711 / 714

页数：4

共 20 条

[1] Prediction of HLA-DQ8 β cell peptidome using a computational program and its relationship to autoreactive T cells [J].

Chang, Kuan Y. ;

Unanue, Emil R. .

INTERNATIONAL IMMUNOLOGY, 2009, 21 (06) :705-713

[2] Islet Amyloid Polypeptide Is a Target Antigen for Diabetogenic CD4+ T Cells [J].

Debug, Thomas ;

Baker, Rocky L. ;

Reisdorph, Nichole ;

Reisdorph, Richard ;

Powell, Roger L. ;

Armstrong, Michael ;

Barbour, Gene ;

Bradley, Brenda ;

Haskins, Kathryn .

DIABETES, 2011, 60 (09) :2325-2330

[3] Diabetogenic T-Cell Clones Recognize an Altered Peptide of Chromogranin A [J].

Delong, Thomas ;

Baker, Rocky L. ;

He, Jing ;

Barbour, Gene ;

Bradley, Brenda ;

Haskins, Kathryn .

DIABETES, 2012, 61 (12) :3239-3246

[4] Autoantigenesis: the evolution of protein modifications in autoimmune disease [J].

Doyle, Hester A. ;

Mamula, Mark J. .

CURRENT OPINION IN IMMUNOLOGY, 2012, 24 (01) :112-118

[5] Chromogranin A is a T cell antigen in human type 1 diabetes [J].

Gottlieb, Peter A. ;

Delong, Thomas ;

Baker, Rocky L. ;

Fitzgerald-Miller, Lisa ;

Wagner, Rebecca ;

Cook, Gabrielle ;

Rewers, Marian R. ;

Michels, Aaron ;

Haskins, Kathryn .

JOURNAL OF AUTOIMMUNITY, 2014, 50 :38-41

[6] Immune recognition of a human renal cancer antigen through post-translational protein splicing [J].

Hanada, K ;

Yewdell, JW ;

Yang, JC .

NATURE, 2004, 427 (6971) :252-256

[7] Pathogenic T-cell clones in autoimmune diabetes: More lessons from the NOD mouse [J].

Haskins, K .

ADVANCES IN IMMUNOLOGY, VOL 87, 2005, 87 :123-162

[8] Processing of synthetic pro-islet amyloid polypeptide (proIAPP) 'amylin' by recombinant prohormone convertase enzymes, PC2 and PC3, in vitro [J].

Higham, CE ;

Hull, RL ;

Lawrie, L ;

Shennan, KIJ ;

Morris, JF ;

Birch, NP ;

Docherty, K ;

Clark, A .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2000, 267 (16) :4998-5004

[9] The insulin A-chain epitope recognized by human T cells is posttranslationally modified [J].

Mannering, SI ;

Harrison, LC ;

Williamson, NA ;

Morris, JS ;

Thearle, DJ ;

Jensen, KP ;

Kay, TWH ;

Rossjohn, J ;

Falk, BA ;

Nepom, GT ;

Purcell, AW .

JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (09) :1191-1197

[10] Recognition of Posttranslationally Modified GAD65 Epitopes in Subjects With Type 1 Diabetes [J].

McGinty, John W. ;

Chow, I-Ting ;

Greenbaum, Carla ;

Odegard, Jared ;

Kwok, William W. ;

James, Eddie A. .

DIABETES, 2014, 63 (09) :3033-3040

← 1 2 →