Ak. Barlow et al., EXOGENOUSLY PROVIDED PEPTIDES OF A SELF-ANTIGEN CAN BE PROCESSED INTOFORMS THAT ARE RECOGNIZED BY SELF-T CELLS, The Journal of experimental medicine, 187(9), 1998, pp. 1403-1415
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.