TY - JOUR
T1 - The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes
T2 - Studies in HEL transgenic mice
AU - DiPaolo, Richard J.
AU - Unanue, Emil R.
PY - 2001
Y1 - 2001
N2 - We report a mouse model for the spontaneous development of autoimmune diabetes: the 3A9 T cell receptor (TCR) transgenic mouse, which contains T cells that recognize the 52-61 family of hen egg-white lysozyme (HEL) peptides in the context of MHC class II I-Ak molecules, was bred to the ILK3 mouse, that expresses HEL protein via the rat insulin promoter (RIP). Despite partial tolerance of 3A9 T cells in ILK3 mice, spontaneous diabetes developed in 64% of 3A9xILK3 mice by 20 weeks of age. We provide evidence that APC from peripancreatic nodes have a large content of peptide-MHC complex and stimulate 3A9 T cells. We also report that cross presentation of HEL from beta cells to APC is 26-fold more efficient than presentation of soluble HEL. We previously reported on a biochemical margin of safety, based on the observation that activation of naive 3A9 T cells required 100-fold more peptide-MHC complexes than required for deletion of 3A9 thymocytes. We speculate that the high local density of autologous peptide-MHC complexes can be a determining factor that leads to the activation of autoreactive CD4 T cells and, consequently, to the development of auto-immunity.
AB - We report a mouse model for the spontaneous development of autoimmune diabetes: the 3A9 T cell receptor (TCR) transgenic mouse, which contains T cells that recognize the 52-61 family of hen egg-white lysozyme (HEL) peptides in the context of MHC class II I-Ak molecules, was bred to the ILK3 mouse, that expresses HEL protein via the rat insulin promoter (RIP). Despite partial tolerance of 3A9 T cells in ILK3 mice, spontaneous diabetes developed in 64% of 3A9xILK3 mice by 20 weeks of age. We provide evidence that APC from peripancreatic nodes have a large content of peptide-MHC complex and stimulate 3A9 T cells. We also report that cross presentation of HEL from beta cells to APC is 26-fold more efficient than presentation of soluble HEL. We previously reported on a biochemical margin of safety, based on the observation that activation of naive 3A9 T cells required 100-fold more peptide-MHC complexes than required for deletion of 3A9 thymocytes. We speculate that the high local density of autologous peptide-MHC complexes can be a determining factor that leads to the activation of autoreactive CD4 T cells and, consequently, to the development of auto-immunity.
KW - Antigen presentation
KW - Autoimmunity
KW - Cross-presentation
KW - Diabetes
KW - Tolerance
UR - http://www.scopus.com/inward/record.url?scp=0035668524&partnerID=8YFLogxK
U2 - 10.1002/1521-4141(200112)31:12<3453::AID-IMMU3453>3.0.CO;2-H
DO - 10.1002/1521-4141(200112)31:12<3453::AID-IMMU3453>3.0.CO;2-H
M3 - Article
C2 - 11745364
AN - SCOPUS:0035668524
VL - 31
SP - 3453
EP - 3459
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 12
ER -