Positive selection is limited by available peptide-dependent MHC conformations

Area of Science:

• Immunology
• Molecular Biology
• T cell biology

Background:

• T cell repertoire diversity is shaped by self peptides presented during thymic development.
• A specific defect in T cell response (H-2K-restricted response to OVA in bm8 mice) was previously observed.
• This defect, termed a 'hole in the immunological repertoire', suggested a potential absence of a critical selecting self peptide.

Purpose of the Study:

• To investigate if the 'hole in the immunological repertoire' in bm8 mice is due to the lack of a specific self peptide.
• To identify peptides capable of restoring positive selection of T cells in bm8 mice.
• To understand the role of self peptides in shaping T cell receptor diversity and MHC molecule conformation.

Main Methods:

• Utilized established criteria for identifying positive selection ligands.
• Tested for the restoration of positive selection of OT-I transgenic T cells (OVA-specific, H-2K-restricted) in bm8 mice using identified peptides.
• Analyzed the effect of peptides on MHC (H-2K) conformation using MHC-specific antibodies.

Main Results:

• Identified specific peptides that restored positive selection of OT-I thymocytes in bm8 mice.
• Demonstrated that the T cell repertoire can be limited by the requirement for specific self peptides during thymic development.
• Showed that peptides can influence MHC conformation, affecting ligand diversity both directly and indirectly.

Conclusions:

• Self peptide diversity is essential for selecting a broad range of T cells.
• The absence of specific self peptides can create 'holes' in the T cell repertoire.
• Peptides play a dual role in T cell selection by varying side chains and modulating MHC conformation.