Elimination of self-peptide major histocompatibility complex class I reactivity in NOD and beta 2-microglobulin-negative mice.
Nonobese diabetic (NOD) mice and beta 2-microglobulin-gene-ablated mice (beta 2M -/-) show impaired presentation of major histocompatibility complex (MHC) class I and self-peptides, structures now recognized as critical for T-cell education to endogenous peptides. The naturally occurring NOD class I presentation abnormality appears to be attributable to, in part, a quantitative defect in the production of Tap-1 mRNA; Tap-1 with Tap-2 normally functions as a transporter for stable self-peptide and class I assembly. This study attempts to reverse NOD and beta 2-M -/- mouse autoreactivity by introduced or reestablished syngeneic class I presentation. Introduction of MHC class I and self-peptides on syngeneic MHC class I-matched cells specifically prevented diabetes in NOD mice and eliminated in vitro class I-directed T-cell autoreactivity in NOD and beta 2M -/- mice. Reestablishment of endogenous class I and self-peptide presentation in NOD mice was achieved with two well-described cures for the NOD mouse, complete Freund's adjuvant and mouse hepatitis virus. Both treatments induced Tap-1 mRNA, reestablished class I presentation of endogenous antigens, and eliminated in vitro and in vivo T-cell autoreactivity of self-peptides in the class I groove. These results substantiate a therapeutic role of self-peptide complexed with class I for T-cell education and suggest that some well-described NOD treatments may work, in part, through reestablishment of tolerance through class I and self-peptide.
Huang
R
R
Immunobiology Laboratory, Massachusetts General Hospital-East, Charlestown 02129, USA.
Guo
J
J
Li
X
X
Faustman
D L
DL
D000375:Aging / Q000276:immunology; D000818:Animals; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D006517:Murine hepatitis virus / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D013045:Species Specificity; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics
D015395:Histocompatibility Antigens Class I; D010455:Peptides; D001613:beta 2-Microglobulin