{"title":"Comprehensive αβ T-Cell Receptor Repertoire Analysis Reveals a Unique CD8+ TCR Landscape in DOCK8-Deficient Patients.","authors":"Ceren Bozkurt,Gökhan Cildir,Umran Aba,Rahmi Kutay Erdogan,Nicholas I Warnock,Chung Hoow Kok,Asena Pinar Sefer,Sule Haskologlu,Sidem Didar Tekeoglu,Gülşah Merve Kılınç,Canberk Ipsir,Tugba Arikoglu,Aylin Kont Ozhan,Saliha Esenboga,Ahmet Özen,Elif Karakoç-Aydiner,Sevgi Bilgiç Eltan,Çigdem Aydogmus,Candan Islamoglu,Kübra Baskın,Betul Karaatmaca,Ayse Metin,Deniz Çagdaş,Figen Dogu,Aydan Ikinciogullari,Safa Baris,Baran Erman","doi":"10.1111/all.16580","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nDedicator 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 characterized by susceptibility to infections, autoimmunity, and a severe Th2-type immune response. While dysfunction in various T cell subsets has been implicated in these phenotypes, a comprehensive analysis of the T-cell receptor (TCR) repertoire in these patients has not yet been documented. This study investigates the αβ TCR repertoire in DOCK8-deficient patients to identify features related to disease pathogenesis and explore the potential role of TCR repertoire alterations in disease development.\r\n\r\nMETHODS\r\nWe 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).\r\n\r\nRESULTS\r\nDifferent 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.\r\n\r\nCONCLUSION\r\nOur study represents the most comprehensive immune repertoire analysis in DOCK8 deficiency. The identification of a significantly restricted αβ TCR repertoire, along with the detection of potentially autoreactive clones, highlights the crucial role of immune repertoire profiling in elucidating the pathogenesis of DOCK8 deficiency.","PeriodicalId":122,"journal":{"name":"Allergy","volume":"25 1","pages":""},"PeriodicalIF":12.0000,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Allergy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/all.16580","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
引用次数: 0
Abstract
BACKGROUND
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 characterized by susceptibility to infections, autoimmunity, and a severe Th2-type immune response. While dysfunction in various T cell subsets has been implicated in these phenotypes, a comprehensive analysis of the T-cell receptor (TCR) repertoire in these patients has not yet been documented. This study investigates the αβ TCR repertoire in DOCK8-deficient patients to identify features related to disease pathogenesis and explore the potential role of TCR repertoire alterations in disease development.
METHODS
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).
RESULTS
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.
CONCLUSION
Our study represents the most comprehensive immune repertoire analysis in DOCK8 deficiency. The identification of a significantly restricted αβ TCR repertoire, along with the detection of potentially autoreactive clones, highlights the crucial role of immune repertoire profiling in elucidating the pathogenesis of DOCK8 deficiency.
期刊介绍:
Allergy is an international and multidisciplinary journal that aims to advance, impact, and communicate all aspects of the discipline of Allergy/Immunology. It publishes original articles, reviews, position papers, guidelines, editorials, news and commentaries, letters to the editors, and correspondences. The journal accepts articles based on their scientific merit and quality.
Allergy seeks to maintain contact between basic and clinical Allergy/Immunology and encourages contributions from contributors and readers from all countries. In addition to its publication, Allergy also provides abstracting and indexing information. Some of the databases that include Allergy abstracts are Abstracts on Hygiene & Communicable Disease, Academic Search Alumni Edition, AgBiotech News & Information, AGRICOLA Database, Biological Abstracts, PubMed Dietary Supplement Subset, and Global Health, among others.