Linked suppression in peripheral T cell tolerance to the house dust mite derived allergen Der p 1.
BACKGROUND
Peripheral tolerance is required to maintain balance within the immune system. A feature of peripheral tolerance is linked suppression, in which tolerance induced to a single T cell epitope inhibits the response to all epitopes in the same protein. It is suggested that this phenomenon is mediated by regulatory T cells through either the activity of immunopressive cytokines or direct cell contact. In previous experiments we failed to detect inhibitory cytokines when T cells from mice rendered tolerant by intranasal delivery of the immunodominant peptide of Der p 1 (p 1, 110-131) were restimulated with peptide in vitro. Therefore, the aim of this study was to determine if cognate interactions between T cells mediated by Notch/Delta signaling induce and maintain peripheral T cell tolerance.


METHODS
Using in situ hybridization and viral mediated gene transfer, the expression and function of Delta1 were investigated in a murine model of T cell tolerance to Der p 1 in vivo.


RESULTS
Delta1 expression is increased on peripheral T cells during the induction of tolerance with high-dose peptide delivered intranasally and when tolerant animals are rechallenged under immunogenic conditions. Peptide p 1, 110-131-specific CD4+ T cells transfected with Delta1 inhibited the response of antigen-primed T cells and induced linked suppression.


CONCLUSIONS
High-dose peptide delivered intranasally induces transient expression of Delta 1 on inhibitory CD4+ T cells. Ligation of the Notch1 receptor on neighbouring T cells by Delta1+ regulatory T cells inhibits clonal expansion of the former and mediates linked suppression.
Hoyne
G F
GF
Respiratory Medicine Unit, Edinburgh University Medical School, Edinburgh, UK.
Dallman
M J
MJ
Lamb
J R
JR
D000485:Allergens / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides; D018604:Epitope Mapping; D006023:Glycoproteins / Q000276:immunology*; D006967:Hypersensitivity / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008925:Mites; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000485:Allergens; D039741:Antigens, Dermatophagoides; D006023:Glycoproteins; D010446:Peptide Fragments