CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

Abstract

Regulatory T cells are critical for maintaining immune tolerance. Recent studies have confirmed their therapeutic suppressive potential to modulate immune responses in organ transplant and autoimmune diseases. However, the unknown and nonspecific antigen recognition of polyclonal Tregs has impaired their therapeutic potency in initial clinical findings. To address this limitation, antigen specificity can be conferred to Tregs by engineering the expression of transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR). In contrast to TCR Tregs, CAR Tregs are major histocompatibility complex (MHC) independent and less dependent on interleukin-2 (IL-2). Furthermore, CAR Tregs maintain Treg phenotype and function, home to the target tissue and show enhanced suppressive efficacy compared to polyclonal Tregs. Additional development of engineered CAR Tregs is needed to increase Tregs' suppressive function and stability, prevent CAR Treg exhaustion, and assess their safety profile. Further understanding of Tregs therapeutic potential will be necessary before moving to broader clinical applications. Here, we summarize recent studies utilizing CAR Tregs in modulating immune responses in autoimmune diseases, transplantation, and gene therapy and future clinical applications.

Keywords: CAR Treg; autoimmune disease; engineered Tregs; gene therapy; transplantation.

Figure 1

Generation of chimeric antigen receptor regulatory T cells (CAR Tregs). CAR Tregs are generated by transduction of polyclonal Tregs with CAR construct (left) or cotransduction of T cells with CAR construct and forkhead box P3 (FoxP3) gene (right).