NOT 门对 T 细胞活化和生长影响的详细分析

MHC class-I-regulated constructs display robust modularity, functioning well with a variety of activators-both CARs and TCRs-and blocker antigens encoded by different HLA class I alleles. We explore the details of activation, proliferation and cytotoxicity of the Tmod technology, focusing on a HER2 construct, but generalizing the conclusions by experiments with other Tmod constructs.

We show that Tmod cells exhibit potent, selective tumor-killing even when surrounded by class-I-expressing cells in 3-dimensional spheroids in vitro and in the mouse body. This behavior is largely ligand-dependent, though there are small ligand-independent effects which are mainly ascribed to mechanisms other than the ITIM sequences of the LIR-1 blocker.

These detailed studies demonstrate that most of Tmod regulation is ligand dependent. Expression levels of the CAR affect activation/proliferation in a LIR-1 NOT gate, but the ITIM signaling module plays only a minor role in ligand-independent activity.