CD40 ligation in the presence of self-reactive CD8 T cells leads to severe immunopathology.
Previous work has shown that stimulation of APCs via CD40 strongly influences the outcome of a CD8 T cell response. In this study, we examined the effect of CD40 ligation on peripheral tolerance induction of self-reactive CD8 T cells in an adoptive transfer model. Naive CD8 T cells from TCR-transgenic (tg) mice specific for the gp33 epitope of lymphocytic choriomeningitis virus were tolerized when transferred into H8-tg mice expressing the gp33 epitope under the control of a MHC class I promoter. However, if the H8 recipient mice were treated with agonistic anti-CD40 Abs, TCR-tg cells vigorously proliferated, and induced destruction of lymphoid organs and hepatitis. Break of peripheral tolerance induction was B cell independent and did not require CD28/B7 interactions. These findings provide further in vivo evidence for the crucial role of the activation state of the APC in peripheral tolerance induction and suggest the need for caution in systemically activating APC via CD40 ligation in the presence of self-reactive T cells.
Roth
Evelyn
E
Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.
Schwartzkopff
Johannes
J
Pircher
Hanspeter
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics; D018106:CD28 Antigens / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000637:transplantation
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D018122:B7-1 Antigen; D001425:Bacterial Outer Membrane Proteins; D018106:CD28 Antigens; D019013:CD40 Antigens; C055700:H.8 protein (Neisseria); D016693:Receptors, Antigen, T-Cell, alpha-beta