Patients with CD3G mutations reveal a role for human CD3g in Treg diversity and suppressive function

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Rowe, Jared H and Delmonte, Ottavia M and Keles, Sevgi and Stadinski, Brian D and Dobbs, Adam K and Henderson, Lauren A and Yamazaki, Yasuhiro and Allende Martínez, Luis Miguel and Bonilla, Francisco A and González Granado, Luis Ignacio and Celikbilek Celik, Seyma and Guner, Sukru N and Kapakli, Hasan and Yee, Christina and Pai, Sung-Yun and Huseby, Eric S and Reisli, Ismail and Regueiro González-Barros, José Ramón and Notarangelo, Luigi D (2018) Patients with CD3G mutations reveal a role for human CD3g in Treg diversity and suppressive function. Blood, 131 (21). pp. 2335-2344. ISSN 1528-0020; 0006-4971

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Official URL: https://doi.org/10.1182/blood-2018-02-835561



Abstract

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, 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 CD3g 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 was used to study composition and diversity of the T-cell receptor b (TRB) repertoire in regulatory T cells (Tregs), conventional CD41 (Tconv), and CD81 T cells from 6 patientswith CD3Gmutations and healthy controls. Treg function was assessed by studying its 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 positions 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.


Item Type:Article
Uncontrolled Keywords:mutation, t-lymphocytes, amino acids, genes, cd3 antigens, autoimmunity, phenotype, regulatory t-lymphocytes, t-cell receptor, deficiency, immune
Subjects:Medical sciences > Medicine > Immunology
Medical sciences > Medicine > Oncology
ID Code:69180
Deposited On:16 Dec 2021 10:00
Last Modified:16 Dec 2021 10:00

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