TCR affinity and negative regulation limit autoimmunity.
Autoimmune diseases are often mediated by self-reactive T cells, which must be activated to cause immunopathology. One mechanism, known as molecular mimicry, proposes that self-reactive T cells may be activated by pathogens expressing crossreactive ligands. Here we have developed a model to investigate how the affinity of the T-cell receptor (TCR) for the activating agent influences autoimmunity. Our model shows that an approximately fivefold difference in the TCR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TCR-ligand affinity to approximately 20 times lower than normal does not induce autoimmunity despite the unexpected induction of cytotoxic T lymphocytes (CTLs) and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response.
Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Matthew A
MA
Gronski
Jonathan M
JM
Boulter
Demetrius
D
Moskophidis
Linh T
LT
Nguyen
Kaisa
K
Holmberg
Alisha R
AR
Elford
Elissa K
EK
Deenick
Hee O
HO
Kim
Josef M
JM
Penninger
Bernhard
B
Odermatt
Awen
A
Gallimore
Nicholas R J
NR
Gascoigne
Pamela S
PS
Ohashi
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D049109:Cell Proliferation; D002860:Chromium Radioisotopes; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D018716:Molecular Mimicry / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D002860:Chromium Radioisotopes; D008024:Ligands; D011948:Receptors, Antigen, T-Cell