机构：[1]Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, California, USA.[2]Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California, USA.[3]Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.[4]Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.[5]Health Sciences Institute, China Medical University, Shenyang, China.[6]Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Reproductive Medicine, Shanghai, China.[7]Department of Medicine/Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.
The ectonucleotidase CD39 functions as a checkpoint in purinergic signaling on effector T cells. By depleting eATP and initiating the generation of adenosine, it impairs memory cell development and contributes to T cell exhaustion, thereby causing defective tumor immunity and deficient T cell responses in older adults who have increased CD39 expression. Tuning enzymatic activity of CD39 and targeting the transcriptional regulation of ENTPD1 can be used to modulate purinergic signaling. Here, we describe that STAT6 phosphorylation downstream of IL-4 signaling represses CD39 expression on activated T cells by inducing a transcription factor network including GATA3, GFI1, and YY1. GATA3 suppresses ENTPD1 transcription through prevention of RUNX3 recruitment to the ENTPD1 promoter. Conversely, pharmacological STAT6 inhibition decreases T cell effector functions via increased CD39 expression, resulting in the defective signaling of P2X receptors by ATP and stimulation of A2A receptors by adenosine. Our studies suggest that inhibiting the STAT6 pathway to increase CD39 expression has the potential to treat autoimmune disease while stimulation of the pathway could improve T cell immunity.
基金：
NIH [R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, P01 HL129941, R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191]; US Department of Veterans Affairs; Palo Alto Veterans Institute for Research
第一作者机构：[1]Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, California, USA.[2]Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California, USA.[3]Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
共同第一作者：
通讯作者：
通讯机构：[1]Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, California, USA.[2]Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California, USA.[4]Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.[7]Department of Medicine/Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.[*1]Mayo Clinic, 200 1st ST SW, Rochester, Minnesota 55905, USA.
医学