Patients with mutations reveal a role for human CD3γ in T diversity and suppressive function.

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, , , and gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor β (TRB) repertoire in regulatory T cells (Ts), conventional CD4 (T), and CD8 T cells from 6 patients with mutations and healthy controls. T function was assessed by studying its ability to suppress proliferation of T cells. T cells of patients with defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of T cells from patients with deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.