Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients.
Proinsulin is a key autoantigen in type 1 diabetes. Evidence in the mouse has underscored the importance of the insulin B chain region in autoimmunity to pancreatic beta cells. In man, a majority of proteasome cleavage sites are predicted by proteasome cleavage algorithms within this region. To study CD8+ T cell responses to the insulin B chain and adjacent C peptide, we selected 8- to 11-mer peptides according to proteasome cleavage patterns obtained by digestion of two peptides covering proinsulin residues 28 to 64. We studied their binding to purified HLA class I molecules and their recognition by T cells from diabetic patients. Peripheral blood mononuclear cells from 17 of 19 recent-onset and 12 of 13 long-standing type 1 diabetic patients produced IFN-gamma in response to proinsulin peptides as shown by using an ELISPOT assay. In most patients, the response was against several class I-restricted peptides. Nine peptides were recognized within the proinsulin region covering residues 34 to 61. Four yielded a high frequency of recognition in HLA-A1 and -B8 patients. Three peptides located in the proinsulin region 41-51 were shown to bind several HLA molecules and to be recognized in a high percentage of diabetic patients.
Toma
Andréa
A
Institut National de la Santé et de la Recherche Médicale U561, Hôpital Cochin-Saint Vincent de Paul, Université Paris V, 75014 Paris, France.
Haddouk
Samy
S
Briand
Jean-Paul
JP
Camoin
Luc
L
Gahery
Hanne
H
Connan
Francine
F
Dubois-Laforgue
Danielle
D
Caillat-Zucman
Sophie
S
Guillet
Jean-Gérard
JG
Carel
Jean-Claude
JC
Muller
Sylviane
S
Choppin
Jeannine
J
Boitard
Christian
C
D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011384:Proinsulin / Q000276:immunology* / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D011384:Proinsulin