Deconstructing the peptide-MHC specificity of T cell recognition

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• T cell receptors (TCRs) must recognize a vast universe of major histocompatibility complex (MHC)-presented peptides, exceeding T cell repertoire diversity.
• TCR cross-reactivity is hypothesized as a mechanism for this recognition, but experimental validation remains limited.

Purpose of the Study:

• To experimentally measure the nature and extent of TCR cross-reactivity.
• To develop a system for identifying MHC-presented peptide ligands recognized by TCRs.
• To computationally identify microbial and self-ligands for human autoimmune TCRs.

Main Methods:

• Utilized yeast-displayed peptide-MHC libraries for TCR selection.
• Employed deep sequencing to analyze selected peptide-MHC ligands.
• Developed computational methods based on TCR recognition motifs.

Main Results:

• Identified hundreds of reactive peptides for five different mouse and human TCRs.
• Observed conserved TCR recognition motifs in selected peptides, resembling known antigens.
• Demonstrated computational identification of activating microbial and self-ligands for autoimmune TCRs.

Conclusions:

• The mechanistic basis of TCR cross-reactivity involves conserved structural recognition surfaces.
• This conserved recognition enables effective surveillance of diverse foreign and self-antigens.
• Degenerate recognition of nonhomologous peptides is not necessary for broad antigen surveillance.