Epitope-dependent inhibition of T cell activation by the Ea transgene: an explanation for transgene-mediated protection from murine lupus.
A high level expression of the Ea(d) transgene encoding the I-E alpha-chain is highly effective in the suppression of lupus autoantibody production in mice. To explore the possible modulation of the Ag-presenting capacity of B cells as a result of the transgene expression, we assessed the ability of the transgenic B cells to activate Ag-specific T cells in vitro. By using four different model Ag-MHC class II combinations, this analysis revealed that a high transgene expression in B cells markedly inhibits the activation of T cells in an epitope-dependent manner, without modulation of the I-E expression. The transgene-mediated suppression of T cell responses is likely to be related to the relative affinity of peptides derived from transgenic I-E alpha-chains (Ealpha peptides) vs antigenic peptides to individual class II molecules. Our results support a model of autoimmunity prevention based on competition for Ag presentation, in which the generation of large amounts of Ealpha peptides with high affinity to I-A molecules decreases the use of I-A for presentation of pathogenic self-peptides by B cells, thereby preventing excessive activation of autoreactive T and B cells.
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Eduardo
E
Martinez-Soría
Nabila
N
Ibnou-Zekri
Masahiro
M
Iwamoto
Marie-Laure
ML
Santiago-Raber
Shuichi
S
Kikuchi
Marie
M
Kosco-Vilbois
Shozo
S
Izui
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen