The P70-84 peptide (also called 5/4E8 epitope) of the human cartilage proteoglycan
(PG) aggrecan is the dominant/arthritogenic epitope in both humans and arthritis-prone
BALB/c mice (PG-induced arthritis, PGIA). An elevated T cell reactivity was demonstrated
to a citrullinated version of the P70-84 epitope in most of the patients with rheumatoid
arthritis (RA). The goal of this study was to understand better how a T cell epitope,
if citrullinated, may affect antigenicity/arthritogenicity in PGIA, a murine model
of RA. T cell reactivity to differentially citrullinated versions of either the human
PG aggrecan P70-84 peptide or the corresponding mouse sequence was assessed in peptide
or aggrecan-immunized and arthritic BALB/c mice as well as in T cell receptor transgenic
mice specific for peptide P70-84 sequence. Peripheral T cell responses were induced
by priming BALB/c mice with either the human wild-type or its citrullinated versions.
Unexpectedly, priming with the citrullinated self-peptide induced a higher T cell
response compared to the wild-type sequence (p<0.001), and the citrullination of the
human peptide abolished T cell reactivity in PGIA. Our data suggest that T cells reactive
to the citrullinated P70-84 peptide escaped thymic selection and are present in the
peripheral T cell repertoire. Results of this study provide evidence that citrullination
of an immunodominant T cell epitope may substantially alter, either increase or abolish,
T cell recognition at the periphery in an experimental model of arthritis.
