Comprehensive alpha and beta T cell repertoire analysis reveals a unique CD8+ TCR landscape in DOCK8-deficient patients

Dedicator of cytokinesis protein 8 (DOCK8) is a guanine nucleotide exchange factor highly expressed in and critical for the function of various innate and adaptive immune cells. DOCK8 deficiency leads to combined immunodeficiency and a severe Th2-type immune response. While dysfunction in different T cell subsets has been reported, a comprehensive analysis of the T cell receptor (TCR) repertoire in these patients has not been documented. We compared immune repertoire profiles determined by high-throughput TCR sequencing of circulating CD4+ and CD8+ T cells from patients with DOCK8 deficiency (n=10) to healthy controls (n=7) and patients with Ataxia-telangiectasia (AT) (n=5), a distinct immunodeficiency syndrome characterized by a restricted TCR repertoire. Different diversity analyses revealed a restricted TRA and TRB repertoire in both CD4+ and CD8+ T cells from DOCK8-deficient patients, with the restriction being more pronounced in CD8+ T cells. Skewed usage of individual variable (V) and joining (J) genes and potentially self-reactive CD8+ T cell clones, as determined by hydrophobicity and cysteine indices, were identified in DOCK8-deficient patients.