Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis
Summary
We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation. Screening of canonical ADAM17 substrates yielded a minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of a receptor following T cell activation-termed activation-induced release (AIR). Embedding AIR into tonic-signaling CARs reduced basal CAR expression proportional to the degree of tonic signa
Content
# Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis
*Published: 2026 May 15*
We sought to endow T cell autonomous regulation of cell surface protein
expression by exploiting the conditional proteolytic activity of ADAM17
following T cell activation. Screening of canonical ADAM17 substrates yielded a
minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of
a receptor following T cell activation-termed activation-induced release (AIR).
Embedding AIR into tonic-signaling CARs reduced basal CAR expression
proportional to the degree of tonic signaling induced, curtailing exhaustion and
improving antitumor potency. In non-tonic signaling CARs, AIR decreased
activation-induced cell death and enhanced T cell expansion after stimulation.
AIR's modularity supports higher-order logic-gating; AIR-regulated peptide masks
enable antigen-dependent unmasking of an EGFR-targeting CAR. Finally, CRISPR
knockin of AIR into endogenous FAS or TGFBR2 endowed them with
activation-induced shedding, which enhanced tumor clearance while preserving
signaling in non-activating conditions. AIR is a compact switch that provides
fast, autonomous regulation of surface proteins for next-generation cell
therapies.
DOI: 10.1016/j.cell.2026.04.037