Exhaustion of CD39-Expressing CD8+ T Cells in Crohn's Disease Is Linked to Clinical Outcome

Gastroenterology. 2022 Oct;163(4):965-981.e31. doi: 10.1053/j.gastro.2022.06.045. Epub 2022 Jun 20.


Background & aims: Exhaustion of CD8 T cells has been suggested to inform different clinical outcomes in Crohn's disease, but detailed analyses are lacking. This study aimed to identify the role of exhaustion on a single-cell level and identify relevant CD8 T cell populations in Crohn's disease.

Methods: Blood and intestinal tissue from 58 patients with Crohn's disease (active disease or remission) were assessed for CD8 T cell expression of exhaustion markers and their cytokine profile by highly multiplexed flow and mass cytometry. Key disease-associated subsets were sorted and analyzed by RNA sequencing. CD39 inhibition assays were performed in vitro.

Results: Activated CD39+ and CD39+PD-1+ CD8 T cell subsets expressing multiple exhaustion markers were enriched at low frequency in active Crohn's disease. Their cytokine production capacity was inversely linked to the Harvey-Bradshaw Index. Subset-level protein and transcriptome profiling revealed co-existence of effector and exhaustion programs in CD39+ and CD39+ PD-1+CD8 T cells, with CD39+ cells likely originating from the intestine. CD39 enzymatic activity controlled T cell cytokine production. Importantly, transcriptional exhaustion signatures were enriched in remission in CD39-expressing subsets with up-regulation of TOX. Subset-level transcriptomics revealed a CD39-related gene module that is associated with the clinical course.

Conclusions: These data showed a role for the exhaustion of peripheral CD39-expressing CD8 T cell subsets in Crohn's disease. Their low frequency illustrated the utility of single-cell cytometry methods for identification of relevant immune populations. Importantly, the link of their exhaustion status to the clinical activity and their specific gene signatures have implications for exhaustion-based personalized medicine approaches.

Keywords: Crohn’s Disease; IBD; Systems Immunology; T Cell Exhaustion; Transcriptome Signature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apyrase* / blood
  • Apyrase* / genetics
  • Apyrase* / immunology
  • Biomarkers / blood
  • CD8-Positive T-Lymphocytes* / immunology
  • Crohn Disease* / blood
  • Crohn Disease* / genetics
  • Crohn Disease* / immunology
  • Cytokines / immunology
  • Humans
  • Prognosis
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocyte Subsets


  • Biomarkers
  • Cytokines
  • Programmed Cell Death 1 Receptor
  • Apyrase
  • ENTPD1 protein, human