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.
Gronski
Matthew A
MA
Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Boulter
Jonathan M
JM
Moskophidis
Demetrius
D
Nguyen
Linh T
LT
Holmberg
Kaisa
K
Elford
Alisha R
AR
Deenick
Elissa K
EK
Kim
Hee O
HO
Penninger
Josef M
JM
Odermatt
Bernhard
B
Gallimore
Awen
A
Gascoigne
Nicholas R J
NR
Ohashi
Pamela S
PS
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