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

Research output: Contribution to journalArticlepeer-review

Authors

  • 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
  • Patrick R. Burkett
  • Jason D. Buenrostro
  • Orit Rozenblatt-Rosen
  • Ana C. Anderson
  • Aviv Regev
  • Vijay K. Kuchroo

Colleges, School and Institutes

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 cancer. 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.

Details

Original languageEnglish
Pages (from-to)454–459
Number of pages6
JournalNature
Volume558
Issue number7710
Early online date13 Jun 2018
Publication statusPublished - 21 Jun 2018

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