The heterogeneity and sexual-dimorphism of human TCRαβ+CD4–CD8–double negative T cells

Dan Tian; Fengcui Qian; Lehan Pan; Mingxue Yin; Bihan Liu; Yuxi Zhang; Xiaobao Yang; Lu Yang; Guangyong Sun; Zhongtao Zhang; Songlin Wang; Patrick S.C. Leung; M. Eric Gershwin; Chunquan Li; Dong Zhang

doi:10.1016/j.jgg.2026.04.008

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The heterogeneity and sexual-dimorphism of human TCRαβ⁺CD4^–CD8^–double negative T cells

doi: 10.1016/j.jgg.2026.04.008

a. Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
b. State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
c. National Clinical Research Center for Digestive Diseases, Beijing 100050, China;
d. The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Changsha, Hunan 421001, China;
e. Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China;
f. Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China;
g. Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China;
h. Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis , CA 95616 , USA

Funds:

This study was supported by the National Natural Science Foundation of China (82270606, 82171823, 62572223, and 62301246), R&

D Program of Beijing Municipal Education Commission (KZ202210025036), Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20220103), Chinese Institutes for Medical Research, Beijing (CX24PY16), Reform and Development Program of Beijing Institute of Respiratory Medicine (Ggyfz202403), Youth Beijing Scholar (035), Beijing Nova Program (20240484501), Beijing Natural Science Foundation (7232035), and Distinguished Young Scholars from Beijing Friendship Hospital (yyqcjh2022-4). The authors express their sincere gratitude to the donors of peripheral blood: Song Wang, Guangyong Sun, Dan Tian, Xue Dong, Shiyang Huang, Zihan Zhang, Xinye Cui, Dongming Li, Bihan Liu, and Xiaonan Du.

Received Date: 2025-08-08
Accepted Date: 2026-04-13
Rev Recd Date: 2026-04-10

Available Online: 2026-04-22

Abstract

Abstract

TCRαβ⁺ double negative T (DNT) cells are increasingly being recognized for their critical roles in the progression of various diseases. However, the molecular and functional signatures remain poorly understood and controversial. In this study, we characterize the single-cell transcriptome, TCR repertoire, and chromatin accessibility of peripheral DNT cells from 10 healthy donors. Naïve, regulatory, cytotoxic, antibody-dependent cell-mediated cytotoxicity, and helper-like DNT cell subsets exhibit specific gene expression, transcriptome regulation, development signature, and sexual heterogeneity, respectively. Using publicly available data, we observe changes in the proportion and gene expression of DNT cell subsets, especially the helper subset, in patients with ulcerative colitis and type 1 diabetes. Overall, human DNT cells exhibit phenotypic and functional diversity, providing a valuable framework for understanding the development and progression of immune-related diseases.
- TCRαβ⁺ double negative T cells,
- Single-cell transcriptome,
- TCR repertoire,
- Chromatin accessibility,
- Sexual heterogeneity

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References

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