T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity.
T cells causing autoimmunity must escape tolerance. We observed that CD8(+) T cells with high avidity for an antigen expressed in the pancreas, kidney, and thymic medulla were efficiently removed from a polyclonal repertoire by central and peripheral tolerance mechanisms. However, both mechanisms spared low-avidity T cells from elimination. Neither the introduction of activated, self-antigen-specific CD4(+) helper T cells nor a global inflammatory stimulus were sufficient to activate the low-avidity CD8(+) T cells and did not break tolerance. In contrast, challenge with a recombinant bacterium expressing the self antigen primed the low-avidity T cells, and the animals rapidly developed autoimmune diabetes. We suggest that whereas thymic and peripheral tolerance mechanisms remove cells that can be primed by endogenous amounts of self antigen, they do not guard against tissue destruction by low-avidity effector T cells, which have been primed by higher amounts of self antigen or by crossreactive antigens.
Zehn
Dietmar
D
Department of Immunology, Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
Bevan
Michael J
MJ
D000818:Animals; D000915:Antibody Affinity / Q000276:immunology*; D000941:Antigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010047:Ovalbumin / Q000276:immunology; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D007143:Immunoglobulin Heavy Chains; D010047:Ovalbumin