Induction and transcriptional regulation of the co-inhibitory gene module in T cells

Norio Chihara, Asaf Madi, Takaaki Kondo, Huiyuan Zhang, Nandini Acharya, Meromit Singer, Jackson Nyman, Nemanja D. Marjanovic, Monika S. Kowalczyk, Chao Wang, Sema Kurtulus, Travis Law, Yasaman Etminan, James Nevin, Christopher D. Buckley, Patrick R. Burkett, Jason D. Buenrostro, Orit Rozenblatt-Rosen, Ana C. Anderson (), Aviv Regev () and Vijay K. Kuchroo ()
Additional contact information
Norio Chihara: Harvard Medical School and Brigham and Women’s Hospital
Asaf Madi: Harvard Medical School and Brigham and Women’s Hospital
Takaaki Kondo: Harvard Medical School and Brigham and Women’s Hospital
Huiyuan Zhang: Harvard Medical School and Brigham and Women’s Hospital
Nandini Acharya: Harvard Medical School and Brigham and Women’s Hospital
Meromit Singer: Broad Institute of MIT and Harvard
Jackson Nyman: Broad Institute of MIT and Harvard
Nemanja D. Marjanovic: Broad Institute of MIT and Harvard
Monika S. Kowalczyk: Broad Institute of MIT and Harvard
Chao Wang: Harvard Medical School and Brigham and Women’s Hospital
Sema Kurtulus: Harvard Medical School and Brigham and Women’s Hospital
Travis Law: Broad Institute of MIT and Harvard
Yasaman Etminan: Harvard Medical School and Brigham and Women’s Hospital
James Nevin: Harvard Medical School and Brigham and Women’s Hospital
Christopher D. Buckley: Rheumatology Research Group, Center for Translational Inflammation Research, Queen Elizabeth Hospital
Patrick R. Burkett: Harvard Medical School and Brigham and Women’s Hospital
Jason D. Buenrostro: Broad Institute of MIT and Harvard
Orit Rozenblatt-Rosen: Broad Institute of MIT and Harvard
Ana C. Anderson: Harvard Medical School and Brigham and Women’s Hospital
Aviv Regev: Broad Institute of MIT and Harvard
Vijay K. Kuchroo: Harvard Medical School and Brigham and Women’s Hospital

Nature, 2018, vol. 558, issue 7710, 454-459

Abstract: Abstract The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4+ T cells promotes autoimmunity, whereas sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer1,2. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.

Date: 2018
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DOI: 10.1038/s41586-018-0206-z

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