Comprehensive Profiling of T- and B-Cell Receptor Repertoires Demonstrates Impaired Developmental and Activation of Adaptive Immunity in DOCK8 Deficiency

Dedicator of cytokinesis protein 8 (DOCK8) is a crucial regulator for the formation of immune synapses, allowing for a proper function of innate and adaptive immune systems. DOCK8 deficiency is a primary immunodeficiency, currently known as Inborn Errors of Immunity (IEI) affecting both cellular and humoral immunity, thus leading to various clinical presentations ranging from infections, autoimmunity, inflammations and malignancies. We aimed to identify unique molecular signatures in the adaptive immune repertoire of DOCK8-deficient patients through comprehensive sequencing and analysis of the T-cell receptor (TCR) and B-cell receptor (BCR) repertoires, correlating these signatures with clinical features of the patients, ultimately providing a "fingerprint" of both individual's immunological status and disease conditions. We characterized the TCR repertoires of αβ T- and γδ T-cells, together with BCR repertoires of B-cells, in peripheral blood of 13 patients and age matched healthy donor controls using next generation sequencing. TCR repertoire in patients with DOCK8 deficiency demonstrated restricted diversity and clonal expansions, favorable use of specific gene in the V-D-J recombination process, and a unique finding of longer complementarity-determining-region-3 (CDR3) length, revealing an impaired T-cell development and activation. Furthermore, BCR repertoire demonstrated high diversity without clonal expansions, portraying an abnormal B-cell development leading to a possible mechanism for atopy and autoimmunity, alongside inadequate activation in DOCK8 deficiency. Lastly, various DOCK8 mutations demonstrated a more profound defects in immune repertoire. These findings expand our knowledge on the role DOCK8 plays in shaping the TCR and BCR repertoires in DOCK8 deficiency.