Sm. Anderton et al., ACTIVATION OF T-CELLS RECOGNIZING SELF 60-KD HEAT-SHOCK PROTEIN CAN PROTECT AGAINST EXPERIMENTAL ARTHRITIS, The Journal of experimental medicine, 181(3), 1995, pp. 943-952
Lewis rats are susceptible to several forms of experimental arthritis-
induced using heat-killed Mycobarterium tuberculosis (adjuvant arthrit
is, or AA), streptococcal cell walls, collagen type II, and the lipoid
al amine CP20961. Prior immunization with the mycobacterial 65-kD heat
shock protein (hsp65) was reported to protect against AA, and other a
thritis models not using M. tuberculosis, via a T cell-mediated mechan
ism. Hsp65 shares 48% amino acid identity with mammalian hsp60, which
is expressed at elevated levels in inflamed synovia. Several studies h
ave reported cross-reactive T cell recognition of mycobacterial hsp65
and self hsp60 in arthritic and normal individuals. We previously desc
ribed nine major histocompatibility complex class II-restricted epitop
es in mycobacterial hsp65 recognized by Lewis rat T cells. Of these on
ly one, covering the 256-270 sequence, primed for cross-reactive T cel
l responses to the corresponding region of rat hsp60. Here we have tes
ted each hsp65 epitope for protective activity by immunizing rats with
synthetic peptides. A peptide containing the 256-270 epitope, which i
nduced cross-reactive T cells, was the only one able to confer protect
ion against AA. Similarly, administration of a T cell line specific fo
r this epitope protected against AA. Preimmunization with the 256-270
epitope induced T cells that responded to heat-shocked syngeneic antig
en-presenting cells, and also protected against CP20961-induced arthri
tis, indicating that activation of T cells recognizing an epitope in s
elf hsp60 can protect against arthritis induced without mycobacteria.
Therefore, in contrast to the accepted concept that cross-reactive T c
ell recognition of foreign and self antigens might induce aggressive a
utoimmune disease, we propose that cross-reactivity between bacterial
and self hsp60 might also be used to maintain a protective self-reacti
ve T cell population. This discovery might have important implications
for understanding T cell-mediated regulation of inflammation.