Patients with CD3G mutations reveal a role for human CD3γ in Treg diversity and suppressive function

Jared H. Rowe, Ottavia M. Delmonte, Sevgi Keles, Brian D. Stadinski, Adam K. Dobbs, Lauren A. Henderson, Yasuhiro Yamazaki, Luis M. Allende, Francisco A. Bonilla, Luis I. Gonzalez-Granado, Seyma Celikbilek Celik, Sukru N. Guner, Hasan Kapakli, Christina Yee, Sung-Yun Pai, Eric S. Huseby, Ismail Reisli, Jose R. Regueiro and Luigi D. Notarangelo

Key points

  • CD3γ-deficient patients manifest T cell phenotypic and functional defects, that are especially prominent in regulatory T (Treg) cells

  • The peripheral T cell repertoire of CD3γ-deficient patients is restricted, with molecular signatures of self-reactivity


Integrity of the T cell receptor/CD3 (TCR/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, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G 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 CD3G associated with autoimmunity. High throughput sequencing (HTS) was used to study composition and diversity of the T cell receptor β (TRB) repertoire in Treg, conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying their ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at position 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.

  • Submitted February 23, 2018.
  • Accepted April 9, 2018.