Human islet T cells are highly reactive to preproinsulin in 1 diabetes

被引：60

作者：

Anderson, Amanda M. ^{[1
]}

Landry, Laurie G. ^{[1
]}

Alkanani, Aimon A. ^{[1
]}

Pyle, Laura ^{[1
,2
]}

Powers, Alvin C. ^{[3
,4
,5
]}

Atkinson, Mark A. ^{[6
]}

Mathews, Clayton E. ^{[6
]}

Roep, Bart O. ^{[7
,8
]}

Michels, Aaron W. ^{[1
,9
,10
]}

Nakayama, Maki ^{[1
,9
,10
]}

机构：

[1] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Sch Med, Aurora, CO 80045 USA

[2] Univ Colorado, Dept Biostat & Informat, Sch Publ Hlth, Aurora, CO 80045 USA

[3] Vanderbilt Univ, Dept Med, Div Diabet Endocrinol & Metab, Med Ctr, Nashville, TN 37232 USA

[4] Vet Affairs Tennessee Valley Healthcare Syst, Med Serv, Nashville, TN 37212 USA

[5] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA

[6] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA

[7] Beckman Res Inst City Hope, Diabet & Metab Res Inst, Dept Diabet Immunol, Duarte, CA 91010 USA

[8] Leiden Univ, Dept Internal Med, Med Ctr, NL-2300 RC Leiden, Netherlands

[9] Univ Colorado, Dept Pediat, Sch Med, Aurora, CO 80045 USA

[10] Univ Colorado, Dept Immunol & Microbiol, Sch Med, Aurora, CO 80045 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2021年 / 118卷 / 41期

关键词：

type; 1; diabetes; CD8 T cells; antigens; epitopes; insulin; HLA CLASS-I; TYPE-1; AUTOANTIGEN; GENETICS; EPITOPES; INSULIN; PROINSULIN; CHILDREN; ONSET; SUSCEPTIBILITY;

D O I：

10.1073/pnas.2107208118

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：

Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.

引用

页数：12

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