Enhanced T cell responses contribute to the genetic predisposition of CD8-mediated spontaneous autoimmunity.
A number of factors have been demonstrated to influence the induction of pathogenic autoimmune responses, including the loss of regulatory T cells. To assess the contribution of regulatory T cells in CD8(+) T cell-mediated autoimmunity, RIP-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic beta-islet cells, together with T cells expressing an LCMV-gp-specific T cell receptor (TCR), were crossed to RAG 2-deficient mice. The loss of potentially regulatory T cells, however, did not contribute to diabetes induction. Surprisingly, both RIP-gp/P14-RAG(+/-) and RIP-gp/P14-RAG(-/-) developed spontaneous disease, suggesting an influence of the 129 genetic background on disease susceptibility. Further studies demonstrated that disease susceptibility was not due to nonspecific T cell activation, nor to enhanced cross-presentation of LCMV-gp, nor to decreased expression levels of the negative regulatory molecule CD5. Disease susceptibility did associate, however, with enhanced T cell responses. Thus, T cell hyperactivity combined with various genetic factors may predispose an individual to autoimmunity.
Garza
Kristine M
KM
Department of Medical Biophysics, Ontario Cancer Institute, Toronto, Canada. kgarza@utep.edu
McKall-Faienza
Kim J
KJ
Otheki
Tashiaki
T
Zakarian
Arsen
A
Odermatt
Bernhard
B
Ohashi
Pamela S
PS
D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
D000956:Antigens, Viral; D001324:Autoantigens; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D007328:Insulin; D010446:Peptide Fragments; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C064655:V(D)J recombination activating protein 2; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus