Figure 1. Putting the brakes or gas on T cell function. Inhibitory chimeric antigen receptors (iCARs) put the brakes on T cell function upon encountering off-target cells. The iCAR is made up of an antigen-specific single-chain variable fragment (scFv) fused to a T cell inhibitory signaling domain. The CAR is made up of an antigen-specific scFV fused to a T cell-activating domain. Cells expressing a tumor-associated antigen (antigen A) but not a normal-tissue antigen (antigen B) would induce T cell activation (solid line), cytotoxicity and cytokine signaling to kill the on-target cells (I.1). In contrast, in cells expressing both antigen A
and antigen B, the iCAR would inhibit CAR-induced or T cell receptor (TCR)-induced T cell activation and prevent subsequent cytotoxicity and cytokine signaling to spare the off-target cells (I.2).

Co-stimulatory chimeric antigen receptors (CCRs) were used to ramp up T cell function when encountering on-target cells. The CAR or TCR used is designed to show low affinity for its antigen. In this scenario, cells expressing antigen A (such as a tumor-associated antigen that might also be found on normal tissue) but not antigen B (such as a tumor-associated antigen) would only show suboptimal T cell activation (dashed line) and lack cytotoxicity and cytokine signaling toward off-target cells (II.1). In cells expressing both antigen A and antigen B, the CCR would help to induce CAR-mediated or TCR-mediated T cell activation and result in cytotoxicity and cytokine signaling to eliminate the on-target cells (II.2)