Peptides Derived From Insulin Granule Proteins Are Targeted by CD8 + T Cells Across MHC Class I Restrictions in Humans and NOD Mice - Archive ouverte HAL Access content directly
Journal Articles Diabetes Year : 2020

Peptides Derived From Insulin Granule Proteins Are Targeted by CD8 + T Cells Across MHC Class I Restrictions in Humans and NOD Mice

(1, 2) , (1, 2) , (1, 2) , (1, 2) , (3) , (1, 2) , (1, 2) , (1, 2, 4) , (1, 2, 5) , (5) , (5) , (6) , (7) , (1, 2, 4) , (1, 2, 4) , (8) , (9) , (3) , (1, 2) , (4, 1)
1
2
3
4
5
6
7
8
9
Georgia Afonso
S. You
Roberto Mallone

Abstract

The antigenic peptides processed by β-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from β-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.

Dates and versions

inserm-03312401 , version 1 (02-08-2021)

Identifiers

Cite

Marie Eliane Azoury, Mahmoud Tarayrah, Georgia Afonso, Aurore Pais, Maikel Colli, et al.. Peptides Derived From Insulin Granule Proteins Are Targeted by CD8 + T Cells Across MHC Class I Restrictions in Humans and NOD Mice. Diabetes, 2020, 69 (12), pp.2678-2690. ⟨10.2337/db20-0013⟩. ⟨inserm-03312401⟩
41 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More