Chimeric cytokine receptor provides IL-2 signaling for engineered regulatory T cell therapy

Abstract Regulatory T cells (Tregs) are potent immune suppressors and critical to the maintenance of immunological tolerance. Interleukin 2 (IL-2) is essential for Treg survival, expansion, phenotypic stability, and suppressive function. However, Tregs do not produce IL-2 and are dependent on exogenous sources of IL-2. This poses a significant challenge for Treg cell therapies in tissues with no or limited IL-2 availability in the microenvironment. Therefore, we have developed engineered Treg cells containing a chimeric cytokine receptor that provides an IL-2 signal. The chimeric cytokine receptor, termed IL-9 tethered switch receptor (IL-9TSR), consists of interleukin 9 (IL-9) tethered to the extracellular domain of IL9RA paired with the intracellular domain of IL2RB. We have shown that Tregs expressing IL-9TSR can survive and expand in the absence of exogenous IL-2 in vitro and in vivo but require TCR stimulation for prolonged persistency. IL-9TSR Tregs have a stable FOXP3 +HELIOS +phenotype and superior suppressive function when compared to control Tregs. In conclusion, we have generated Treg cells engineered to survive and function in a low IL-2 environment. Treg cell therapies equipped with IL-2 signaling enable increased persistency and allow for potential use in more clinical indications than previously possible.