Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Human leucocyte antigen B*27 (HLA-B*27) is strongly associated with inflammatory diseases like ankylosing spondylitis (AS) and acute anterior uveitis (AAU).
• The precise mechanism by which HLA-B*27 contributes to disease pathogenesis remains unclear.
• A potential mechanism involves the presentation of pathogenic peptides to CD8+ T cells.

Purpose of the Study:

• To investigate the role of T cell receptors (TCRs) in HLA-B*27-associated inflammatory diseases.
• To identify specific peptides that activate disease-associated TCRs.
• To elucidate the structural basis of TCR cross-reactivity in the context of HLA-B*27.

Main Methods:

• Isolation of orphan TCRs with a disease-associated BV9-CDR3β motif from patients with AS and AAU.
• Analysis of TCR chain pairing (AV21) and clonal expansion in affected tissues.
• Utilizing HLA-B*27:05 yeast display peptide libraries to screen for activating peptides.
• Structural analysis of TCR-peptide-MHC interactions.

Main Results:

• TCRs with a specific BV9-CDR3β motif and AV21 chain pairing were identified and clonally expanded in AS and AAU patients.
• These TCRs were activated by both self-peptides and microbial peptides presented by HLA-B*27:05.
• Structural analysis revealed a shared binding motif in these peptides that engages the BV9-CDR3β TCRs, explaining cross-reactivity.

Conclusions:

• The findings support a hypothesis where both microbial and self-antigens contribute to the pathogenesis of HLA-B*27-associated inflammatory diseases.
• TCR cross-reactivity, driven by shared peptide motifs, is a key factor in disease development.
• This study provides insights into the molecular mechanisms underlying HLA-B*27-related conditions.