Peer-reviewedCC BYCell death & disease
TNFAIP8 polarity proteins mediate T cell development by propagating lipid second messenger signaling in thymocytes.
15 affiliations
- 1Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China.
- 2Henan International Joint Laboratory of Immunology and Model Animals, School of Medical Technology, Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China.
- 3Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China.
- 4School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China.
- 5Center of Translational Medicine, Zibo Central Hospital, Shandong University, Zibo, China.
- 6School of Basic Medical Sciences, Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China.
- 7Department of Radiation Oncology, The First Affiliated Hospital of Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China.
- 8Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, China. [email protected].
- 9Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China. [email protected].
- 10Henan International Joint Laboratory of Immunology and Model Animals, School of Medical Technology, Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China. [email protected].
- 11Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China. [email protected].
- 12School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China. [email protected].
- 13Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China. [email protected].
- 14Henan International Joint Laboratory of Immunology and Model Animals, School of Medical Technology, Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China. [email protected].
- 15Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Henan Medical University (original name: Xinxiang Medical University), Xinxiang, China. [email protected].
Abstract
T lymphocytes are primarily generated in the thymus through a complex process of positive and negative selections. The molecular mechanisms underlying this process are not fully understood. Here, we report that TNFAIP8 (TNF-α-induced protein 8-like) family of polarity proteins mediates T cell development by propagating phosphoinositide signaling in the thymus. Genetic deletion of hematopoietic members of the TNFAIP8 family resulted in dramatic reductions in thymus size, cellularity, and corticomedullary differentiation. Total thymocyte counts in Tnfaip8-deficient mice were reduced by more than 50%, which was associated with marked reductions in T cell numbers in blood and in secondary lymphoid organs, as compared to wild-type mice. Bone marrow chimeric experiments revealed that the thymic developmental defect was hematopoietic cell-intrinsic. TNFAIP8 proteins controlled double negative (DN) thymocyte proliferation and metabolism during positive selection by promoting PI3K-AKT/mTOR signaling through phosphoinositide second messengers. Pharmaceutical activation of AKT partially rectified the thymic developmental defect of Tnfaip8-deficient mice. Thus, TNFAIP8 polarity proteins are essential for thymic development of T lymphocytes, and genetic or pharmaceutical manipulation of the TNFAIP8 pathway may be useful for controlling T lymphocyte-mediated immunity.
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BibTeX
@article{gao2026tnfaip8,
title = {{TNFAIP8 polarity proteins mediate T cell development by propagating lipid second messenger signaling in thymocytes.}},
author = {Jingtao Gao and Cun Guo and Yang Lv and Han Wang and Sheng Chen and Peili Zhuang and Miaomiao Song and Xueqin Tian and Shan Jiang and Wei Lu and Lu Zhang and Peiqing Zhao and Xiaohan Wu and Xiangfeng Song and Xiaohong Kang and Youhai H Chen and Tingmin Chang and Hui Wang and Yunwei Lou},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09100-6},
url = {https://europepmc.org/article/MED/42907424},
note = {CC BY},
}
RIS
TY - JOUR
TI - TNFAIP8 polarity proteins mediate T cell development by propagating lipid second messenger signaling in thymocytes.
AU - Jingtao Gao
AU - Cun Guo
AU - Yang Lv
AU - Han Wang
AU - Sheng Chen
AU - Peili Zhuang
AU - Miaomiao Song
AU - Xueqin Tian
AU - Shan Jiang
AU - Wei Lu
AU - Lu Zhang
AU - Peiqing Zhao
AU - Xiaohan Wu
AU - Xiangfeng Song
AU - Xiaohong Kang
AU - Youhai H Chen
AU - Tingmin Chang
AU - Hui Wang
AU - Yunwei Lou
PY - 2026
DA - 2026/07/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09100-6
UR - https://europepmc.org/article/MED/42907424
AB - T lymphocytes are primarily generated in the thymus through a complex process of positive and negative selections. The molecular mechanisms underlying this process are not fully understood. Here, we report that TNFAIP8 (TNF-α-induced protein 8-like) family of polarity proteins mediates T cell development by propagating phosphoinositide signaling in the thymus. Genetic deletion of hematopoietic members of the TNFAIP8 family resulted in dramatic reductions in thymus size, cellularity, and corticomedullary differentiation. Total thymocyte counts in Tnfaip8-deficient mice were reduced by more than 50%, which was associated with marked reductions in T cell numbers in blood and in secondary lymphoid organs, as compared to wild-type mice. Bone marrow chimeric experiments revealed that the thymic developmental defect was hematopoietic cell-intrinsic. TNFAIP8 proteins controlled double negative (DN) thymocyte proliferation and metabolism during positive selection by promoting PI3K-AKT/mTOR signaling through phosphoinositide second messengers. Pharmaceutical activation of AKT partially rectified the thymic developmental defect of Tnfaip8-deficient mice. Thus, TNFAIP8 polarity proteins are essential for thymic development of T lymphocytes, and genetic or pharmaceutical manipulation of the TNFAIP8 pathway may be useful for controlling T lymphocyte-mediated immunity.
SN - 2041-4889
ER -