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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss of Siglec expression on T lymphocytes during human evolution
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Loss of Siglec expression on T lymphocytes during human evolution

机译：人类进化过程中T淋巴细胞的Siglec表达缺失

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We report here that human T cells give much stronger proliferative responses to specific activation via the T cell receptor (TCR) than those from chimpanzees, our closest evolutionary relatives. Nonspecific activation using phytohemagglutinin was robust in chimpanzee T cells, indicating that the much lower response to TCR simulation is not due to any intrinsic inability to respond to an activating stimulus. CD33-related Siglecs are inhibitory signaling molecules expressed on most immune cells and are thought to down-regulate cellular activation pathways via cytosolic immunoreceptor tyrosine-based inhibitory motifs. Among human immune cells, T lymphocytes are a striking exception, expressing little to none of these molecules. In stark contrast, we find that T lymphocytes from chimpanzees as well as the other closely related "great apes" (bonobos, gorillas, and orangutans) express several CD33-related Siglecs on their surfaces. Thus, human-specific loss of T cell Siglec expression occurred after our last common ancestor with great apes, potentially resulting in an evolutionary difference with regard to inhibitory signaling. We confirmed this by studying Siglec-5, which is prominently expressed on chimpanzee lymphocytes, including CD4T cells. Ab-mediated clearance of Siglec-5 from chimpanzee T cells enhanced TCR-mediated activation. Conversely, primary human T cells and Jurkat cells transfected with Siglec-5 become less responsive; i.e., they behave more like chimpanzee T cells. This human-specific loss of T cell Siglec expression associated with T cell hyperactivity may help explain the strikingly disparate prevalence and severity of T cell-mediated diseases such as AIDS and chronic active hepatitis between humans and chimpanzees.
机译：我们在这里报告说，与我们最接近的进化亲戚黑猩猩相比，人类T细胞对通过T细胞受体（TCR）进行特异性激活的增殖反应要强得多。使用植物血凝素的非特异性激活在黑猩猩T细胞中很强，表明对TCR模拟的响应要低得多，这并不是由于任何固有的对激活刺激的无能。 CD33相关的Siglecs是在大多数免疫细胞上表达的抑制性信号分子，被认为通过基于胞浆免疫受体酪氨酸的抑制性基序下调细胞活化途径。在人类免疫细胞中，T淋巴细胞是一个惊人的例外，几乎不表达这些分子。与之形成鲜明对比的是，我们发现黑猩猩的T淋巴细胞以及其他紧密相关的“大猿”（bon猴，大猩猩和猩猩）在其表面表达了几种与CD33相关的Siglecs。因此，人类特异性T细胞Siglec表达的丧失发生在我们最后一个有大猿猴的祖先之后，可能导致抑制信号的进化差异。我们通过研究Siglec-5证实了这一点，该蛋白在黑猩猩淋巴细胞（包括CD4T细胞）上明显表达。黑猩猩T细胞的Ab介导的Siglec-5清除增强了TCR介导的激活。相反，转染了Siglec-5的原代人T细胞和Jurkat细胞的反应性变差。即它们的行为更像黑猩猩T细胞。与T细胞功能亢进相关的人类特定的T细胞Siglec表达丧失可能有助于解释人类与黑猩猩之间T细胞介导的疾病（例如AIDS和慢性活动性肝炎）截然不同的患病率和严重程度。

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