The T cell antigen receptor (TCR) recognizes peptides from pathogenic proteins bound in the major histocompatibility complex (MHC). To convert this binding event into downstream signaling, the TCR complex contains immunoreceptor tyrosine-based activation motifs (ITAMs) that act as docking sites for the cytoplasmic tyrosine kinase ZAP-70. Unique among antigen receptors, the TCR complex uses 10 ITAMs to transduce peptide-MHC binding to the cell interior. Using synthetic, drug-inducible receptor-ligand pairs, it was found that greater ITAM multiplicity primarily enhanced the efficiency with which ligand binding was converted into an intracellular signal. This manifested as an increase in the fraction of cells that became activated in response to antigen, and a more synchronous initiation of TCR-proximal signaling, rather than direct amplification of the intracellular signals. Exploiting these findings, the potency and selectivity of chimeric antigen receptors targeted against cancer were substantially enhanced by modulating the number of encoded ITAMs.

T细胞抗原受体（TCR）从主要组织相容性复合体（MHC）中结合的致病蛋白中识别肽。为了将此结合事件转化为下游信号，TCR复合物包含基于免疫受体酪氨酸的激活基序（ITAM），充当细胞质酪氨酸激酶ZAP-70的停靠位点。TCR复合物在抗原受体中是独一无二的，它使用10种ITAM来转导肽-MHC与细胞内部的结合。使用合成的，药物诱导的受体-配体对，发现更大的ITAM多样性主要增强了将配体结合转化为细胞内信号的效率。这表现为响应抗原而被激活的细胞比例增加，并且TCR-近端信号传导更同步地启动，而不是直接放大细胞内信号。利用这些发现，通过调节编码的ITAM的数量，大大提高了靶向癌症的嵌合抗原受体的效力和选择性。