YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells

Mumtaz Y Balkhi; Gabor Wittmann; Fang Xiong; Richard P Junghans

doi:10.1016/j.isci.2018.03.009

YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells

iScience. 2018 Apr 27:2:105-122. doi: 10.1016/j.isci.2018.03.009. Epub 2018 Apr 11.

Authors

Mumtaz Y Balkhi¹, Gabor Wittmann², Fang Xiong¹, Richard P Junghans³

Affiliations

¹ Biotherapeutics Development Lab, Division of Hematology/Oncology, Department of Medicine, Tufts University School of Medicine, 800 Washington St, Boston, MA 02111, USA.
² Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Tufts University School of Medicine, Boston, MA, USA.
³ Biotherapeutics Development Lab, Division of Hematology/Oncology, Department of Medicine, Tufts University School of Medicine, 800 Washington St, Boston, MA 02111, USA. Electronic address: rpjunghans@outlook.com.

Abstract

T cells infiltrate affected organs in chronic infections and malignancy, but they may fail to eradicate virus-infected cells or tumor because of exhaustion. This report describes a Yin Yang-1 (YY1)-centered mechanism for diverse components that have been correlated with exhaustion. Utilizing an in vitro reconstruction of chronic T cell activation, YY1 is shown to positively regulate the checkpoint receptors PD1, Lag3, and Tim3 and to negatively regulate the type I cytokines interleukin-2 (IL-2) (in collaboration with Ezh2 histone methyltransferase) and interferon gamma (IFN-?). Other tests suggest that IL-2 failure drives a large component of cytotoxic functional decline rather than solely checkpoint receptor-ligand interactions that have been the focus of current anti-exhaustion therapies. Clinical evaluations confirm elevated YY1 and Ezh2 in melanoma tumor-infiltrating lymphocytes and in PD1+ T cells in patients with HIV. Exhaustion is revealed to be an active process as the culmination of repetitive two-signal stimulation in a feedback loop via CD3/CD28?p38MAPK/JNK?YY1? exhaustion.

Keywords: Cancer Systems Biology; Immune Response; Immune System Disorder.