EXOGENOUSLY PROVIDED PEPTIDES OF A SELF-ANTIGEN CAN BE PROCESSED INTOFORMS THAT ARE RECOGNIZED BY SELF-T CELLS

Major histocompatibility complex (MHC) class II molecules can present peptides derived from two different sources. The predominant source of peptide in uninfected antigen presenting cells (APCs) is from self-pr oteins that are synthesized within the cell and traffic through the MH C class II compartment. The other source of antigen is endocytosed pro teins, which includes both self-and foreign proteins. Foreign protein antigens generate adaptive immune responses, whereas self-peptides sta bilize the MHC class II heterodimer on the cell surface, allowing posi tive and negative selection of thymocytes. Therefore, self-antigens pl ay an important normal role in shaping the T cell receptor repertoire as well as a pathological role in autoimmunity. To determine whether p rocessing and presentation of self-antigens by MHC class II molecules differs depending on whether the antigen is supplied through synthesis within the cell or by endocytosis, we used a T cell clone against an Ea peptide presented by I-Ab to show that processing through these two routes can differ. We also show that mice can be tolerant to the epit ope formed through the endogenous route, but responsive to the epitope that can be formed through endocytosis. This suggests that negative s election occurs primarily against antigens that are synthesized within the APC, and that endocytosed self-antigens could serve as autoantige ns. Finally, we also demonstrate that lipopolysaccharide-activated B c ells are defective for uptake, processing, and presentation of this se lf-antigen, and that this cell-elates with the increased expression of the costimulatory molecules B7.1 and B7.2. This may provide a model f or studying the onset of an autoimmune response.