Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease.
Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8(+) T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.
Lang
Karl S
KS
Institute of Experimental Immunology, University Hospital of Zurich, Schmelzbergstrasse 12, Zurich, Switzerland. karl.lang@usz.ch
Recher
Mike
M
Junt
Tobias
T
Navarini
Alexander A
AA
Harris
Nicola L
NL
Freigang
Stefan
S
Odermatt
Bernhard
B
Conrad
Curdin
C
Ittner
Lars M
LM
Bauer
Stefan
S
Luther
Sanjiv A
SA
Uematsu
Satoshi
S
Akira
Shizuo
S
Hengartner
Hans
H
Zinkernagel
Rolf M
RM
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000821:virology; D005805:Genes, MHC Class I; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors; D019076:Transgenes; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014764:Viral Proteins