TY - JOUR

T1 - Conventional and Neo-antigenic Peptides Presented by beta Cells Are Targeted by Circulating Naive CD8+T Cells in Type 1 Diabetic and Healthy Donors

AU - Gonzalez-Duque, Sergio

AU - Azoury, Marie Eliane

AU - Colli, Maikel L.

AU - Afonso, Georgia

AU - Turatsinze, Jean-Valery

AU - Nigi, Laura

AU - Lalanne, Ana Ines

AU - Sebastiani, Guido

AU - Carre, Alexia

AU - Pinto, Sheena

AU - Culina, Slobodan

AU - Corcos, Noemie

AU - Bugliani, Marco

AU - Marchetti, Piero

AU - Armanet, Mathieu

AU - Diedisheim, Marc

AU - Kyewski, Bruno

AU - Steinmetz, Lars M.

AU - Buus, Soren

AU - You, Sylvaine

AU - Dubois-Laforgue, Daniele

AU - Larger, Etienne

AU - Beressi, Jean-Paul

AU - Bruno, Graziella

AU - Dotta, Francesco

AU - Scharfmann, Raphael

AU - Eizirik, Decio L.

AU - Verdier, Yann

AU - Vinh, Joelle

AU - Mallone, Roberto

PY - 2018

Y1 - 2018

N2 - Although CD8 + T-cell-mediated autoimmune β cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by β cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known β cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8 + T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by β cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.

AB - Although CD8 + T-cell-mediated autoimmune β cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by β cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known β cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8 + T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by β cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.

U2 - 10.1016/j.cmet.2018.07.007

DO - 10.1016/j.cmet.2018.07.007

M3 - Journal article

C2 - 30078552

VL - 28

SP - 946

EP - 960

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 6

ER -