Heat‐shock protein T‐cell epitopes trigger a spreading regulatory control in a diversified arthritogenic T‐cell response

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Abstract
Summary: Adjuvant arthritis (AA) in Lewis rats is T‐cell mediated and seems to depend on T cells recognising the 180–188 epitope of mycobacterial heat‐shock protein (hsp) 60. Analysis of arthritogenic T‐cell clone A2b has revealed a mimicry of this particular epitope with an articular cartilage‐associated target T‐cell epitope. Nasal administration of synthetic peptides covering this 180–188 sequence led to epitope‐.specific tolerance and resistance to AA. Since this tolerisation protocol also inhibited avridine arthritis, one may conclude that this form of epitope‐specific tolerance had effectuated a spreading tolerisation at the level of target antigens that included a diverse set of possible arthritis ‐associated antigens. In vitro anergised T cells exhibited suppressive activity in a co‐culture system. As in this case ‐ depending on the presence of the antigen of the anergic T cell – such T cells suppressed responder T cells of a different antigenic specificity, we postulated that anergic T cells may be responsible for a spreading of tolerance. It seemed that such spreading of tolerance was channelled through the antigen‐presenting cells (APC) and was dependent on direct cell‐cell contact. This and additional forms of spreading of tolerance could be responsible for specific nasal tolerance, causing inhibition of the development of an arthritogenic inflammatory response. This can be similarly che case for the arthritis protection that resulted from immunisation with hsps. Analysis of T‐cell responses following hsp immunisations revealed that the arthritis inhibitory activity resided in T cells with specificity for a conserved part of microbial hsp60. The same T cells cross‐responded to rat self‐hsp60. Low level expression of the latter molecule on non‐professional APC could possibly have induced a suppressive anergic state in these autoreactive cells. Thus, immunisation with microbial hsp would have led to an expansion of such T cells, leading to raised disease‐suppressive potential when selectively trapped and activated in the inflamed self‐hsp‐overexpressing joint. Alternatively the cross‐recognised self‐hsp epitope could have the regulatory qualities of an altered peptide ligand or a partial agonist for T cells that see the microbial homologue as the full agonist.

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