Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors.
Front Endocrinol (Lausanne)
; 12: 622647, 2021.
Article
em En
| MEDLINE
| ID: mdl-33841327
ABSTRACT
Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Precursores de Proteínas
/
Linfócitos T CD4-Positivos
/
Ilhotas Pancreáticas
/
Diabetes Mellitus Tipo 1
/
Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Front Endocrinol (Lausanne)
Ano de publicação:
2021
Tipo de documento:
Article