Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec H2W 1R7, Canada.
Molecular Biology Program, University of Montréal, Montréal, Québec H3T 1J4, Canada.
Sci Immunol. 2022 Aug 5;7(74):eabn6373. doi: 10.1126/sciimmunol.abn6373.
CD2 is largely described to promote T cell activation when engaged by its ligands, CD48 in mice and CD58 in humans, that are present on antigen-presenting cells (APCs). However, both CD48 and CD58 are also expressed on T cells. By generating new knockout mouse strains lacking CD2 or CD48 in the C57BL/6 background, we determined that whereas CD2 was necessary on T cells for T cell activation, its ligand CD48 was not required on APCs. Rather, CD48 was also needed on T cells. One exception was during cytotoxicity, which required CD48 on T cells and APCs. Fluorescence resonance energy transfer (FRET) studies in nonimmune cells provided evidence that cis interactions between CD2 and CD48 existed within individual cells. CD2-CD48 interactions on T cells enabled more robust T cell receptor (TCR) signals, including protein tyrosine phosphorylation. Using T cells from a CD2 knock-in mouse in which a tag was inserted at the carboxyl terminus of CD2, mass spectrometry analyses revealed that the role of CD2 in T cell activation correlated with its ability to interact with components of the TCR complex and the protein tyrosine kinase Lck. CD2-CD58 provided a similar function in human T cells. Thus, our data imply that T cell-intrinsic cis interactions of CD2 with its ligands are required for TCR signaling and T cell activation. Interactions with ligands on APCs contribute during cytotoxicity.
CD2 主要通过与其配体结合来促进 T 细胞的激活，在小鼠中为 CD48，在人类中为 CD58，这些配体存在于抗原呈递细胞 (APC) 上。然而，CD48 和 CD58 也在 T 细胞上表达。通过生成缺乏 CD2 或 CD48 的新敲除小鼠品系，我们确定在 C57BL/6 背景下，CD2 在 T 细胞上对于 T 细胞的激活是必需的，但其配体 CD48 在 APC 上并非必需。相反，CD48 在 T 细胞上也需要。一个例外是细胞毒性，这需要 T 细胞和 APC 上的 CD48。非免疫细胞中的荧光共振能量转移 (FRET) 研究提供了证据，表明 CD2 和 CD48 之间在单个细胞内存在顺式相互作用。T 细胞上的 CD2-CD48 相互作用使 TCR 信号更加强烈，包括蛋白酪氨酸磷酸化。使用在 CD2 羧基末端插入标签的 CD2 敲入小鼠的 T 细胞进行分析，质谱分析表明，CD2 在 T 细胞激活中的作用与其与 TCR 复合物和蛋白酪氨酸激酶 Lck 的成分相互作用的能力相关。CD2-CD58 在人类 T 细胞中提供了类似的功能。因此，我们的数据表明，CD2 与其配体的细胞内顺式相互作用是 TCR 信号和 T 细胞激活所必需的。与 APC 上的配体的相互作用在细胞毒性期间起作用。
