This study describes a TGFβ-induced pathway by which Treg cells suppress the cytotoxic activity of CD8+ T cells by dysregulating the intracellular calcium signaling needed to trigger degranulation. It also provides evidence for an approach to regulate the cytotoxic function of engineered T lymphocytes via highly selective optical control of Ca2+ influx with light-sensitive channelrhodopsin.
Adoptive cell transfer utilizing tumour-targeting cytotoxic T lymphocytes (CTLs) is one of the most effective immunotherapies against haematological malignancies, but significant clinical success has not yet been achieved in solid tumours due in part to the strong immunosuppressive tumour microenvironment. Here, we show that suppression of CTL killing by CD4+CD25+Foxp3+ regulatory T cell (Treg) is in part mediated by TGFbeta-induced inhibition of inositol trisphosphate (IP3) production, leading to a decrease in T cell receptor (TCR)-dependent intracellular Ca2+ response. Highly selective optical control of Ca2+ signalling in adoptively transferred CTLs enhances T cell activation and IFN-gamma production in vitro, leading to a significant reduction in tumour growth in mice. Altogether, our findings indicate that the targeted optogenetic stimulation of intracellular Ca2+ signal allows for the remote control of cytotoxic effector functions of adoptively transferred T cells with outstanding spatial resolution by boosting T cell immune responses at the tumour sites.
Author Info: (1) Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA. (2) Department of
Author Info: (1) Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA. (2) Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA. (3) Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA. (4) Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA. (5) Department of Pharmacology &Physiology, University of Rochester, Rochester, New York 14642, USA. (6) Department of Pharmacology &Physiology, University of Rochester, Rochester, New York 14642, USA. (7) School of Life Sciences, Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea. (8) School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Republic of Korea. (9) School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Republic of Korea. (10) School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Republic of Korea. (11) Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA.
