DISRUPTION OF T-CELL TOLERANCE BY DIRECTING A SELF ANTIGEN TO MACROPHAGE-SPECIFIC SCAVENGER RECEPTORS

Breakdown of immune self tolerance is speculated to cause autoimmune d iseases, but most studies on tolerance use foreign molecules as target s. In this study, we show another approach using delivery of a maleyla ted self protein to macrophage-specific scavenger receptors. Mice gene rate Abs against the maleylated form of a ubiquitous self Ag, mouse se rum albumin (MSA), although native MSA is nonimmunogenic. This generat ion of anti-maleyl MSA Abs depends on binding of maleyl MSA to scaveng er receptors in vivo, since coinjection of a serologically unrelated s cavenger receptor ligand inhibits it, suggesting that the Ab response is T cell dependent. Spleen cells as well as nylon adherence-purified splenic T cells from maleyl MSA-immune mice proliferate in response to both maleyl MSA and MSA; this response is blocked by anti-MHC class I I mAbs, and the autoimmune cells can recognize at least five 15-mer pe ptides from the MSA sequence, establishing that T cell tolerance to MS A has been broken in these mice. Maleyl MSA and MSA are recognized equ ally well, provided the scavenger receptor-specific delivery of maleyl MSA is blocked during stimulation in vitro, indicating that maleyl MS A-specific non-self peptides are unlikely to play a major role in the observed disruption of T cell tolerance. Thus, delivery of some self m olecules to scavenger receptors may lead to disruption of immune toler ance. These results are relevant to mechanisms of immune tolerance and the etiopathogenesis of autoimmunity.