Transgenic inducible MHC I overexpression in mouse alveolar type 2 cells.

IF 2 3区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS
Justine Mathé, Sylvie Brochu, Marc K Saba-El-Leil, Caroline Coté, Amrita Karia, Sébastien Harton, Claude Perreault
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Abstract

The major histocompatibility complex class I (MHC I) is crucial in adaptive immunity, enabling CD8 + T cells to detect and eliminate infected and cancerous cells. Recent studies have uncovered significant variability in MHC I expression across tissues, challenging the traditional belief of uniform expression. Lung epithelial cells (LECs) express meager amounts of MHC I, which preserves the lung epithelium from excessive inflammation but renders it more susceptible to cancer and infection. Despite MHC I overexpression in various immunopathologies, its precise role in disease initiation or progression remains unclear due to the absence of suitable in vivo models for studying MHC I overexpression. This study introduces a novel mouse model with targeted surface MHC I upregulation. Leveraging a conditional Cre-lox system, we augmented Nlrc5 expression to specifically upregulate MHC I in alveolar type 2 (AT2) LECs, known for their low basal expression of MHC I and significant overexpression in disease. Our model demonstrated a rapid and sustained tenfold increase in MHC I surface expression persisting for up to a year without triggering pathology or inflammation. Comprehensive characterization and validation of this model indicated that MHC I overexpression does not serve as a primary initiator of respiratory diseases under steady-state conditions and shows a therapeutic window for increasing MHC I without significant damage to the lung epithelium. This adaptable model offers insights into the effects of tissue-specific MHC I regulation and presents new avenues for therapeutic development.

转基因诱导MHC I在小鼠肺泡2型细胞中的过表达。
主要组织相容性复合体I类(MHC I)在适应性免疫中至关重要,使CD8 + T细胞能够检测和消除感染细胞和癌细胞。最近的研究发现MHC I在各组织中的表达具有显著的变异性,挑战了传统的一致表达的观点。肺上皮细胞(LECs)表达少量的MHC I,它保护肺上皮免受过度炎症,但使其更容易患癌症和感染。尽管MHC I在各种免疫病理中过表达,但由于缺乏合适的体内模型来研究MHC I过表达,其在疾病发生或进展中的确切作用仍不清楚。本研究介绍了一种靶向表面MHC I上调的新型小鼠模型。利用条件Cre-lox系统,我们增强Nlrc5表达,特异性上调肺泡型2 (AT2) LECs的MHC I,以其低基础表达和疾病中显著的过表达而闻名。我们的模型显示MHC I表面表达快速持续增加十倍,持续长达一年而不会引发病理或炎症。该模型的综合表征和验证表明,在稳态条件下,MHC I过表达不是呼吸道疾病的主要引发因素,并且显示出增加MHC I而不显著损害肺上皮的治疗窗口。这种适应性模型提供了对组织特异性MHC I调节的影响的见解,并为治疗发展提供了新的途径。
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来源期刊
Transgenic Research
Transgenic Research 生物-生化研究方法
CiteScore
5.40
自引率
0.00%
发文量
38
审稿时长
4-8 weeks
期刊介绍: Transgenic Research focusses on transgenic and genome edited higher organisms. Manuscripts emphasizing biotechnological applications are strongly encouraged. Intellectual property, ethical issues, societal impact and regulatory aspects also fall within the scope of the journal. Transgenic Research aims to bridge the gap between fundamental and applied science in molecular biology and biotechnology for the plant and animal academic and associated industry communities. Transgenic Research publishes -Original Papers -Reviews: Should critically summarize the current state-of-the-art of the subject in a dispassionate way. Authors are requested to contact a Board Member before submission. Reviews should not be descriptive; rather they should present the most up-to-date information on the subject in a dispassionate and critical way. Perspective Reviews which can address new or controversial aspects are encouraged. -Brief Communications: Should report significant developments in methodology and experimental transgenic higher organisms
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