Comprehensive αβ T-Cell Receptor Repertoire Analysis Reveals a Unique CD8+ TCR Landscape in DOCK8-Deficient Patients

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Dedicator of cytokinesis protein 8 (DOCK8) is crucial for immune cell function.
• DOCK8 deficiency causes combined immunodeficiency with infections, autoimmunity, and Th2 skewing.
• T-cell receptor (TCR) repertoire alterations are implicated but not fully characterized in DOCK8 deficiency.

Purpose of the Study:

• To comprehensively analyze the αβ TCR repertoire in DOCK8-deficient patients.
• To identify TCR repertoire features linked to DOCK8 deficiency pathogenesis.
• To explore the role of TCR repertoire alterations in disease development.

Main Methods:

• High-throughput TCR sequencing of circulating CD4+ and CD8+ T cells.
• Comparison of DOCK8-deficient patients (n=10) with healthy controls (n=7) and ataxia-telangiectasia patients (n=5).
• Analysis of repertoire diversity, V(D)J gene usage, and T cell clone characteristics (hydrophobicity, cysteine indices).

Main Results:

• A restricted TRA and TRB repertoire was observed in both CD4+ and CD8+ T cells of DOCK8-deficient patients.
• Repertoire restriction was more pronounced in CD8+ T cells.
• Skewed V(D)J gene usage and potentially self-reactive CD8+ T cell clones were identified.

Conclusions:

• This study provides the most comprehensive immune repertoire analysis in DOCK8 deficiency to date.
• A significantly restricted αβ TCR repertoire and potentially autoreactive clones were identified.
• Immune repertoire profiling is crucial for understanding the pathogenesis of DOCK8 deficiency.