Trappc1 intrinsically prevents ferroptosis of naive T cells to avoid spontaneous autoinflammatory disease in mice

T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T‐cell development and homeostasis is unknown. Using CD4cre‐Trappc1flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number...

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Published in:European journal of immunology 2024-03, Vol.54 (3), p.e2350836-n/a
Main Authors: Zhang, Zhaoqi, Zhao, Chenxu, Sun, Lingyun, Cheng, Chen, Tian, Qianchuan, Wu, Changhong, Xu, Yanan, Dong, Xue, Zhang, Baojun, Zhang, Lianfeng, Zhao, Yong
Format: Article
Language:English
Subjects:
Acetylcysteine
Adaptive immunity
Adoptive transfer
Animal models
Animals
Autoinflammatory disease
Calcium (intracellular)
CD45 antigen
Cell culture
Cell death
Cell Differentiation
Cell number
Endoplasmic reticulum
Ferroptosis
Golgi apparatus
Hereditary Autoinflammatory Diseases
Homeostasis
Inflammation
Inflammatory diseases
Leukocytes (neutrophilic)
Leukotriene B4
Lipid peroxidation
Lipids
Lymphocytes
Lymphocytes T
Mice
Mice, Knockout
Naive T cells
Oxidative phosphorylation
p53 Protein
Phosphorylation
Prostaglandin E2
Protein folding
Protein transport
Proteins
T-Lymphocytes
Thymus
Trappc1
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Summary:T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T‐cell development and homeostasis is unknown. Using CD4cre‐Trappc1flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number of naive T cells in the periphery, whereas thymic T‐cell development in Trappc1 cKO mice was identical as WT mice. In the culture assays and mouse models with adoptive transfer of the sorted WT (CD45.1+CD45.2+) and Trappc1 cKO naive T cells (CD45.2+) to CD45.1+ syngeneic mice, Trappc1‐deficient naive T cells showed significantly reduced survival ability compared with WT cells. RNA‐seq and molecular studies showed that Trappc1 deficiency in naive T cells reduced protein transport from the endoplasmic reticulum to the Golgi apparatus, enhanced unfolded protein responses, increased P53 transcription, intracellular Ca2+, Atf4‐CHOP, oxidative phosphorylation, and lipid peroxide accumulation, and subsequently led to ferroptosis. Trappc1 deficiency in naive T cells increased ferroptosis‐related damage‐associated molecular pattern molecules like high mobility group box 1 or lipid oxidation products like prostaglandin E2, leukotriene B4, leukotriene C4, and leukotriene D4. Functionally, the culture supernatant of Trappc1 cKO naive T cells significantly promoted neutrophils to express inflammatory cytokines like TNFα and IL‐6, which was rescued by lipid peroxidation inhibitor Acetylcysteine. Importantly, Trappc1 cKO mice spontaneously developed severe autoinflammatory disease 4 weeks after birth. Thus, intrinsic expression of Trappc1 in naive T cells plays an integral role in maintaining T‐cell homeostasis to avoid proinflammatory naive T‐cell death‐caused autoinflammatory syndrome in mice. This study highlights the importance of the TRAPPC in T‐cell biology. Lacking Trappc1 in naive T cells increases the secretion of ferroptosis‐related damage‐associated molecular pattern molecules or lipid oxidation products. This promoted neutrophils to express inflammatory cytokines, leading to severe autoinflammatory diseases in mice.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.202350836