Human T cells recognize HLA-DP-bound peptides in two orientations

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• Human leukocyte antigen (HLA) molecules present peptides to T cells for immune recognition.
• A long-standing dogma posits that peptide binding to HLA molecules occurs in a conserved N- to C-terminal orientation.

Purpose of the Study:

• To investigate the possibility of reversed C- to N-terminal peptide binding to HLA molecules.
• To characterize the molecular basis and immunological relevance of this reversed binding orientation.

Main Methods:

• Large-scale identification of peptides bound to HLA-DP molecules.
• Isolation and characterization of human cytomegalovirus (CMV)-specific CD4+ T cells.
• High-resolution crystal structure determination of an HLA-DP-peptide complex.

Main Results:

• Identification of reverse peptide binding motifs in 9 out of 14 HLA-DP allotypes, indicating C- to N-terminal binding.
• Demonstration that CMV-specific T cells recognize CMV peptides bound to HLA-DP in a reverse orientation.
• Elucidation of the molecular basis for C- to N-terminal peptide binding through crystal structure analysis.

Conclusions:

• HLA-DP molecules exhibit unique features allowing for C- to N-terminal peptide binding.
• This reversed binding orientation expands the repertoire of peptides presented by HLA class II molecules.
• The findings have implications for understanding immune responses against pathogens and cancer.