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Exogenously provided peptides of a self-antigen can be processed into forms that are recognized by self-T cells
1Section of Immunobiology, Yale University School of Medicine, and Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA.
The Journal of Experimental Medicine
|June 6, 1998
Summary
Major histocompatibility complex (MHC) class II molecules present peptides from internal or endocytosed sources. Self-antigens processed differently via these routes can influence T cell tolerance and autoimmunity, with endocytosed antigens potentially acting as autoantigens.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmunity
Background:
- Major histocompatibility complex (MHC) class II molecules present peptides from both intracellular self-proteins and endocytosed proteins.
- Self-peptides are crucial for T cell receptor repertoire selection, while foreign antigens trigger adaptive immunity.
- Dysregulation in self-antigen presentation is implicated in autoimmune diseases.
Purpose of the Study:
- To investigate if processing and presentation of self-antigens by MHC class II molecules differ based on their source (endogenous synthesis vs. endocytosis).
- To explore the implications of differential self-antigen processing on T cell tolerance and the potential for autoimmunity.
Main Methods:
- Utilized a T cell clone specific for an Ealpha peptide presented by I-Ab.
- Compared the processing and presentation of self-antigens derived from endogenous synthesis versus endocytosis.
- Assessed T cell responses and tolerance in mice to epitopes generated through different antigen processing routes.
- Examined antigen processing and presentation in lipopolysaccharide-activated B cells.
Main Results:
- Demonstrated distinct processing pathways for self-antigens depending on whether they originate from intracellular synthesis or endocytosis.
- Showed that mice can exhibit tolerance to endogenously derived epitopes but respond to endocytosed ones.
- Identified that negative selection primarily targets endogenously synthesized antigens.
- Found lipopolysaccharide-activated B cells are defective in processing and presenting a specific self-antigen, correlating with increased B7.1/B7.2 expression.
Conclusions:
- Differential processing of self-antigens via endogenous and endocytic pathways can lead to distinct T cell recognition and tolerance.
- Endocytosed self-antigens may act as autoantigens, contributing to autoimmune responses.
- Defective antigen presentation in activated B cells, coupled with altered costimulatory molecule expression, could model the initiation of autoimmune conditions.