An altered self-peptide with superagonist activity blocks a CD8-mediated mouse model of type 1 diabetes.
T cell tolerance can be experimentally induced through administration of self-peptides with single amino acid substitution (altered peptide ligands or APLs). However, little is known about the effects of APLs on already differentiated autoreactive CD8+ T cells that play a pivotal role in the pathogenesis of autoimmune diabetes. We generated a panel of APLs derived from an influenza virus hemagglutinin peptide exhibiting in vitro functions ranging from antagonism to superagonism on specific CD8+ T cells. A superagonist APL was further characterized for its therapeutic activity in a transgenic mouse model of type 1 diabetes. When injected i.v. 1 day after the transfer of diabetogenic hemagglutinin-specific CD8+ T cells into insulin promoter-hemagglutinin transgenic mice, the superagonist APL proved more effective than the native hemagglutinin peptide in blocking diabetes. This protective effect was associated with an inhibition of CD8+ T cell cytotoxicity in vivo and with a decreased accumulation of these cells in the pancreas, leading to a marked reduction of intrainsulitis. In conclusion, a superagonist "self-peptide" APL was more effective than the native peptide in treating a CD8+ T cell-mediated diabetes model.
Hartemann-Heurtier
Agnès
A
Institut National de la Scientifique et de la Santé Recherche Médicale Unité 546, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Mars
Lennart T
LT
Bercovici
Nadège
N
Desbois
Sabine
S
Cambouris
Christophe
C
Piaggio
Eliane
E
Zappulla
Jacques
J
Saoudi
Abdelhadi
A
Liblau
Roland S
RS
D019264:Adoptive Transfer; D000409:Alanine / Q000378:metabolism; D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D001324:Autoantigens / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism / Q000627:therapeutic use; D005998:Glycine / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology / Q000378:metabolism; D007275:Injections, Intravenous; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000819:agonists* / Q000378:metabolism / Q000627:therapeutic use*
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008024:Ligands; D010446:Peptide Fragments; D000409:Alanine; D005998:Glycine