HIF-1α regulates the expression of the non-conventional isoform of the cd5 gene in T cells under the hypoxic condition: A potential mechanism for CD5neg/low phenotype of infiltrating cells in solid tumors

IF 3.7 4区 医学 Q2 CELL BIOLOGY
Smita Kumari, Srishti Sahu, Bharat Singh, Swarnima Gupta, Amit Kumar Kureel, Ankit Srivastava, Deeksha Rikhari, Sameer Srivastava, Ambak Kumar Rai
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Abstract

CD5, a T-cell receptor (TCR) negative regulator, is reduced on the surface of CD8+ lymphocytes in the tumor microenvironment (TME). Reduced surface CD5 expression (sCD5) occurs due to the preferential transcription of HERV-E derived exon E1B, i.e., a non-conventional form of the cd5 gene instead of its conventional exon E1A. A tumor employs several mechanisms to evade anti-tumor response, and hypoxia is one such mechanism that prevails in the TME and modulates the infiltrated T lymphocytes. We identified hypoxia response elements (HREs) upstream of E1B. We showed binding of HIF-1α onto these HREs and increased E1B mRNA expression in hypoxic T cells. This results in decreased sCD5 expression and increased cytoplasmic accumulation in T cells. We also validated our study in a solid tumor, i.e., colorectal cancer (CRC) patient samples. This hypoxia-driven mechanism reduces the surface CD5 expression on infiltrated T-cells in solid tumors.

Abstract Image

HIF-1α在低氧条件下调节T细胞中cd5基因非常规亚型的表达:实体瘤浸润细胞CD5neg/low表型的潜在机制
CD5是一种T细胞受体(TCR)阴性调节因子,在肿瘤微环境(TME)中的CD8+淋巴细胞表面被还原。表面CD5表达减少(sCD5)是由于HERV-E衍生的外显子E1B的优先转录而发生的,即CD5基因的非常规形式而不是其常规外显子E1 a。肿瘤采用多种机制来逃避抗肿瘤反应,缺氧是TME中普遍存在并调节浸润的T淋巴细胞的机制之一。我们鉴定了E1B上游的缺氧反应元件(HRE)。我们发现HIF-1α与这些HRE结合,并增加缺氧T细胞中E1B mRNA的表达。这导致T细胞中sCD5表达降低和细胞质积累增加。我们还在实体瘤,即癌症(CRC)患者样本中验证了我们的研究。这种缺氧驱动的机制降低了实体瘤中浸润的T细胞表面CD5的表达。
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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