美国国家儿童健康和人类发展研究所Paul E. Love课题组发现，CD3ζ 免疫受体酪氨酸激活基序(ITAM)通过抑制低亲和肽的T细胞抗原受体(TCR)信号传导，来实现配体的识别和拮抗。相关论文于2023年11月9日发表于国际顶尖学术期刊《自然—免疫学》杂志上。

他们使用条件“开关”小鼠模型评估了灭活三个CD3ζ链ITAM对TCR信号传导和T细胞效应反应的影响。出乎意料的是，他们发现T细胞表达含有失活(非信号)CD3ζ ITAMs (6F-CD3ζ)的TCR，表现出区分低亲和力和高亲和力配体的能力降低，导致对低亲和力配体的信号传导和细胞因子反应增强，因为以前未检测到CD3ζ ITAMs的抑制功能。

此外，6F-CD3ζ TCR难以拮抗，正如一个新的硅自适应动力学校对模型所预测的那样，该模型修正了ITAM多样性在TCR信号传导中的作用。最后，表达6F-CD3ζ的T细胞对表达低亲和力配体的实体瘤表现出增强的细胞溶解活性，确定了一种新的反直觉的TCR介导的癌症免疫治疗方法。

据介绍，TCR包含10个ITAM信号序列，分布在6个CD3亚基中;然而，造成这种结构复杂性和多样性的原因尚不清楚。

附：英文原文

Title: CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides

Author: Gaud, Guillaume, Achar, Sooraj, Bourassa, Franois X. P., Davies, John, Hatzihristidis, Teri, Choi, Seeyoung, Kondo, Taisuke, Gossa, Selamawit, Lee, Jan, Juneau, Paul, Taylor, Naomi, Hinrichs, Christian S., McGavern, Dorian B., Franois, Paul, Altan-Bonnet, Grgoire, Love, Paul E.

Issue&Volume: 2023-11-09

Abstract: The T cell antigen receptor (TCR) contains ten immunoreceptor tyrosine-based activation motif (ITAM) signaling sequences distributed within six CD3 subunits; however, the reason for such structural complexity and multiplicity is unclear. Here we evaluated the effect of inactivating the three CD3ζ chain ITAMs on TCR signaling and T cell effector responses using a conditional ‘switch’ mouse model. Unexpectedly, we found that T cells expressing TCRs containing inactivated (non-signaling) CD3ζ ITAMs (6F-CD3ζ) exhibited reduced ability to discriminate between low- and high-affinity ligands, resulting in enhanced signaling and cytokine responses to low-affinity ligands because of a previously undetected inhibitory function of CD3ζ ITAMs. Also, 6F-CD3ζ TCRs were refractory to antagonism, as predicted by a new in silico adaptive kinetic proofreading model that revises the role of ITAM multiplicity in TCR signaling. Finally, T cells expressing 6F-CD3ζ displayed enhanced cytolytic activity against solid tumors expressing low-affinity ligands, identifying a new counterintuitive approach to TCR-mediated cancer immunotherapy. Love and colleagues find an inhibitory function for CD3ζ ITAMs in response to low-affinity ligands, meaning that CD3ζ can perform a dual function in TCR signaling by playing a positive or negative role depending on the affinity of the TCR for its peptide ligand.

DOI: 10.1038/s41590-023-01663-2

Source: https://www.nature.com/articles/s41590-023-01663-2