The arthritogenic T cell receptor and its ligand in a model of spontaneous arthritis.
OBJECTIVE
Spontaneous arthritis in the KRN transgenic mouse model is due to the autoreactivity of the transgenic T cell receptor (TCR) against Ag7 major histocompatibility complex (MHC) molecules, which leads to strong but incomplete clonal deletion. We sought to determine whether other stimuli triggering this receptor might provoke arthritis, whether the apparently systemic reactivity might have some joint-preferential component explaining the paradoxical arthritic phenotype, and whether the transgenic receptor was the only one required or whether other TCRs might be ferried along in a leaky tolerance process.


METHODS
Crosses and radiation chimeras involving a panel of transgenic and knockout mouse lines were used. The reactivity of the KRN TCR was tested in carboxyfluorescein diacetate succinimidyl ester-transfer experiments and in crosses with transgenic or inbred mice expressing other molecules that stimulate the KRN receptor (the mls-1a superantigen, the Aalpha(k69)Abeta(k) mutant MHC molecule). The arthritogenic capacity of T cells expressing only the KRN TCR was tested by crossing to recombination-activating gene-knockout mice, and constructing bone marrow chimeras with precursors to these strictly monoclonal T cells.


RESULTS
The data show that the KRN TCR itself is the only receptor needed. It needs to be triggered by the Ag7 molecule loaded with self-peptides in order to provoke arthritis, but there is no indication of preferential presentation of joint-derived peptides.


CONCLUSIONS
Arthritis can be generated by systemic recognition of self-MHC-peptide complexes by autoreactive T cells. This triggers B lymphocytes to produce arthritogenic antibodies, without the involvement of joint-specific T cell targets.
Mangialaio
S
S
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France.
Ji
H
H
Korganow
A S
AS
Kouskoff
V
V
Benoist
C
C
Mathis
D
D
D000818:Animals; D001168:Arthritis / Q000235:genetics*; D004195:Disease Models, Animal; D000939:Epitopes; D007596:Joints / Q000276:immunology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
D000939:Epitopes; D008024:Ligands; D011948:Receptors, Antigen, T-Cell