Synthetic interleukin-2 receptor-based chemically inducible signaling complex (RCISC)

The synthetic interleukin-2 (IL-2) receptor-based chemically inducible signaling complex is an engineered receptor system designed to provide precise external control over T-cell activity. It typically consists of two chimeric subunits: one containing the IL-2 receptor beta (IL-2Rβ) signaling domain fused to an FK506-binding protein (FKBP) and another containing the common gamma chain (γc) domain fused to the FKBP-rapamycin binding (FRB) fragment of mTOR. In the presence of rapamycin, these two subunits dimerize, mimicking the natural assembly of the IL-2 receptor complex and triggering the JAK/STAT signaling pathway. This system is primarily utilized in adoptive cell therapies, such as CAR-T cells, to allow clinicians to pharmacologically regulate the expansion and persistence of therapeutic cells using an FDA-approved small molecule. By decoupling T-cell proliferation from endogenous IL-2 levels, this technology aims to reduce the toxicity associated with systemic cytokine administration while enhancing the efficacy of cellular immunotherapies against various cancers.

Other names

Rapamycin-inducible IL-2 receptorChemically inducible IL-2 receptorRapamycin-activated IL-2 receptor complexSynthetic IL-2R signaling systemFKBP-FRB IL-2 receptor complex

Rapamycin acts as a molecular bridge that induces the dimerization of synthetic receptor subunits containing FKBP and FRB domains, thereby bringing the intracellular signaling domains of the IL-2 receptor (IL-2Rβ and γc) into proximity to initiate downstream JAK/STAT signaling.