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ORAI3 对于淋巴细胞和巨噬细胞的钙库操纵性钙内流和免疫反应不是必需的。

ORAI3 is dispensable for store-operated Ca2+ entry and immune responses by lymphocytes and macrophages.

机构信息

Department of Pathology, New York University Grossman School of Medicine, New York, NY.

出版信息

J Gen Physiol. 2022 Oct 3;154(10). doi: 10.1085/jgp.202213104. Epub 2022 Jul 21.

DOI:10.1085/jgp.202213104
PMID:35861698
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9532584/
Abstract

Ca2+ signals regulate the function of many immune cells and promote immune responses to infection, cancer, and autoantigens. Ca2+ influx in immune cells is mediated by store-operated Ca2+ entry (SOCE) that results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels. The CRAC channel is formed by three plasma membrane proteins, ORAI1, ORAI2, and ORAI3. Of these, ORAI1 is the best studied and plays important roles in immune function. By contrast, the physiological role of ORAI3 in immune cells remains elusive. We show here that ORAI3 is expressed in many immune cells including macrophages, B cells, and T cells. To investigate ORAI3 function in immune cells, we generated Orai3-/- mice. The development of lymphoid and myeloid cells in the thymus and bone marrow was normal in Orai3-/- mice, as was the composition of immune cells in secondary lymphoid organs. Deletion of Orai3 did not affect SOCE in B cells and T cells but moderately enhanced SOCE in macrophages. Orai3-deficient macrophages, B cells, and T cells had normal effector functions in vitro. Immune responses in vivo, including humoral immunity (T cell dependent or independent) and antitumor immunity, were normal in Orai3-/- mice. Moreover, Orai3-/- mice showed no differences in susceptibility to septic shock, experimental autoimmune encephalomyelitis, or collagen-induced arthritis. We conclude that despite its expression in myeloid and lymphoid cells, ORAI3 appears to be dispensable or redundant for physiological and pathological immune responses mediated by these cells.

摘要

钙离子信号调节许多免疫细胞的功能，并促进对感染、癌症和自身抗原的免疫反应。免疫细胞中的钙离子内流是通过储存操作的钙离子内流 (SOCE) 介导的，这是由于钙离子释放激活的钙离子 (CRAC) 通道的开放。CRAC 通道由三种质膜蛋白 ORAI1、ORAI2 和 ORAI3 组成。在这些蛋白中，ORAI1 研究得最多，在免疫功能中发挥重要作用。相比之下，ORAI3 在免疫细胞中的生理作用仍不清楚。我们在这里表明，ORAI3 在许多免疫细胞中表达，包括巨噬细胞、B 细胞和 T 细胞。为了研究 ORAI3 在免疫细胞中的功能，我们生成了 Orai3-/- 小鼠。Orai3-/- 小鼠的胸腺和骨髓中淋巴样和髓样细胞的发育正常，次级淋巴器官中免疫细胞的组成也正常。ORAI3 的缺失不影响 B 细胞和 T 细胞中的 SOCE，但适度增强了巨噬细胞中的 SOCE。Orai3 缺陷型巨噬细胞、B 细胞和 T 细胞在体外具有正常的效应功能。体内免疫反应，包括体液免疫（T 细胞依赖性或非依赖性）和抗肿瘤免疫，在 Orai3-/- 小鼠中正常。此外，Orai3-/- 小鼠在对败血症休克、实验性自身免疫性脑脊髓炎或胶原诱导性关节炎的易感性方面没有差异。我们得出结论，尽管 ORAI3 在髓样和淋巴样细胞中表达，但它似乎对于这些细胞介导的生理和病理免疫反应是可有可无的或冗余的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a93d/9532584/2f0c592757af/JGP_202213104_FigS10.jpg
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