Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
Department of Pharmacology, Northwestern University, Chicago, IL, USA.
Nat Commun. 2022 Apr 19;13(1):2033. doi: 10.1038/s41467-022-29725-3.
TCR stimulation triggers Ca signals that are critical for T cell function and immunity. Several pore-forming α and auxiliary β subunits of voltage-gated Ca channels (VGCC) were reported in T cells, but their mechanism of activation remains elusive and their contribution to Ca signaling in T cells is controversial. We here identify Caβ1, encoded by Cacnb1, as a regulator of T cell function. Cacnb1 deletion enhances apoptosis and impairs the clonal expansion of T cells after lymphocytic choriomeningitis virus (LCMV) infection. By contrast, Cacnb1 is dispensable for T cell proliferation, cytokine production and Ca signaling. Using patch clamp electrophysiology and Ca recordings, we are unable to detect voltage-gated Ca currents or Ca influx in human and mouse T cells upon depolarization with or without prior TCR stimulation. mRNAs of several VGCC α1 subunits are detectable in human (Ca3.3, Ca3.2) and mouse (Ca2.1) T cells, but they lack transcription of many 5' exons, likely resulting in N-terminally truncated and non-functional proteins. Our findings demonstrate that although Caβ1 regulates T cell function, these effects are independent of VGCC channel activity.
T 细胞受体刺激引发的钙信号对于 T 细胞功能和免疫至关重要。已经在 T 细胞中报道了几种电压门控钙通道（VGCC）的形成孔的 α 和辅助 β 亚基，但它们的激活机制仍然难以捉摸，它们对 T 细胞钙信号的贡献存在争议。在这里，我们确定 Cacnb1 编码的 Caβ1 是 T 细胞功能的调节剂。Cacnb1 缺失增强了细胞凋亡，并损害了淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染后 T 细胞的克隆扩增。相比之下，Cacnb1 对于 T 细胞增殖、细胞因子产生和钙信号传导是可有可无的。通过使用膜片钳电生理学和钙记录，我们无法在人类和小鼠 T 细胞中检测到去极化时的电压门控钙电流或钙内流，无论是否有 TCR 刺激。在人类（Ca3.3、Ca3.2）和小鼠（Ca2.1）T 细胞中可以检测到几种 VGCC α1 亚基的 mRNA，但它们缺乏许多 5' 外显子的转录，可能导致 N 端截短和无功能的蛋白质。我们的发现表明，尽管 Caβ1 调节 T 细胞功能，但这些影响独立于 VGCC 通道活性。
