Could T Cell Exhaustion Be a Useful Marker for Disease Status and Trajectory in Crohn Disease?

laboratory assistant analyzing a blood sample
Researchers sought to understand any association between CD8 T cell exhaustion and clinical outcomes among patients with Crohn disease.

Exhaustion of T cell subsets may be a useful biomarker for personalized medicine approaches in Crohn disease (CD), according to study findings published in Gastroenterology.

Researchers conducted a study at the Albert-Ludwigs-University in Germany, enrolling 58 patients (n=58) with CD and healthy control individuals (n=20), who donated blood samples as well as biopsies of the ileum and colon. Tissues were evaluated for CD8 T cell expression and cytokine profiles using highly multiplexed flow and mass spectrometry; for CD39 inhibition, researchers used an in vitro approach.

Epigenetic T cell exhaustion genesets were able to differentiate between patients with active disease and divergent clinical outcomes from those in remission.

Compared with control individuals, patients with CD had elevated CD39 (P =.0315) expression and decreased CD127 (P =.0268) and Helios expression (P =.0091). Among the patients, those with active disease had higher PD-1 (P =.0332) and CD39 (P =.0001) expression. These data suggested the induction of exhaustion is detectable using T cell profiling.

Significant correlations were observed in PD-1+CD39+ cells between CD8+ and Harvey Bradshaw Index (HBI; r, 0.49; P =.01) and calprotectin levels (r, 0.49; P =.02) and in CD39+ cells between CD8+ and HBI (r, 0.55; P =.003) and calprotectin levels (r, 0.52; P =.01). No correlations were observed in PD1+cells.

After CD8 T cell stimulation, exhausted T cells had disturbed cytokine production of tumor necrosis factor (TNF; P =.0088) and interferon (IFN)-γ (P =.0025) in intestinal tissue. The lowest expression of effector cytokines was observed in samples from patients in remission.

Researchers integrated the single-cell cytokine production profile of exhausted cells into the functional exhaustion score (FES). Increased FES indicated more severe exhaustion. Clinical correlations were observed between HBI and FES in CD39+ (r, 0.41; P =.03) and PD1+CD39+ (r, 0.38; P =.04) cells.

Comparing between samples, the exhaustion signature of CD8 T cells in peripheral blood was related with significant enrichments in CD8 T cell populations expressing CD39 in inflamed intestinal mucosa.

CD39 was found to be a likely checkpoint for driving exhaustion by regulating CD8 T cell cytokine production. After CD39 inhibition, cytokine production in CD39+ CD8 T cells was increased compared with PD1+ (P =.0005) or CD39 (P =.0406) cells.

Using a CD39-related gene signature as a stratification tool was able to differentiate patients that would relapse from those who would not (P <.0001).

Study limitations included a need for prospective clinical trials to compare the study findings to other transcriptome-based treatment.

The study authors concluded, “Our data support a clinically relevant role for the exhaustion of a CD8 T cell subset in CD. Fostering exhaustion may represent a promising novel therapeutic concept. The data also point towards a non-canonical cellular differentiation pathway to exhaustion in CD.”


Globig A-M, Mayer LS, Heeg M, et al. Exhaustion of CD39-expressing CD8+ T cells in Crohn’s disease is linked to clinical outcome. Gastroenterology. Published online June 20, 2022. doi:10.1053/j.gastro.2022.06.045