Expression of Programmed Death-Ligand 1 by Human Colonic CD90+ Stromal Cells Differs Between Ulcerative Colitis and Crohn’s Disease and Determines Their Capacity to Suppress Th1 Cells

Abstract

Background and AimsThe role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses.MethodsTissues and cells derived from Crohn’s disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture.ResultsA significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses.ConclusionWe present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.

Crohn's disease is facilitated by a disturbance of programmed death‐1 ligand 2 on blood dendritic cells

“…22 PD-L2 is generally expressed on antigen-presenting cells including DCs as wells as activated T cells and B cells. 14 We focussed on DCs in the ilea and blood of patients, as previous studies have shown that aggregated PD-L2 on DCs is essential for Th1 immunity 15 which drives CD pathology. 14 We focussed on DCs in the ilea and blood of patients, as previous studies have shown that aggregated PD-L2 on DCs is essential for Th1 immunity 15 which drives CD pathology.…”

“…[23][24][25] A previous study examined PD-L1 and PD-L2 expression on CD90 + stromal cells in human colonic mucosa tissue and found lower expression of PD-L1 but not PD-L2. 14 We focussed on DCs in the ilea and blood of patients, as previous studies have shown that aggregated PD-L2 on DCs is essential for Th1 immunity 15 which drives CD pathology. While we found no differences in PD-L2 levels in the ilea from CD patients with controls, flow cytometry studies of blood DCs showed increased levels of PD-L2 while microscopy confirmed the protein is aggregated.…”

Immunological differences between colorectal cancer and normal mucosa uncover a prognostically relevant immune cell profile

“…20,37 Similarly, PD-L1 was shown to be decreased in the inflamed mucosa of Crohn's disease patients with increased IFNγ levels. 38 Induced colitis experiments in mice showed that IFNγ is one of the most highly induced mediators in the inflamed gut. 39 This indicates that IFNγ is part of the tumor-induced inflammatory response and fits the idea that cancer is a chronic stimulus for the immune system.…”

T‐bet interferes with PD‐1/PD‐L1‐mediated suppression of CD4+ T cell inflammation and survival in Crohn's disease

“…Interestingly, a recent study demonstrated that the colonic CD90 + stromal cells from Crohn's disease patients presented significantly lower PD‐L1, together with reduced capacity to suppress Th1 inflammation . Reduction of the PD‐1/PD‐L1 signaling thus appears to be a common mechanism through which the inflammation in Crohn's disease persists over time.…”

“…that T-bet, as the Th1-associated transcription factor, displayed significantly higher expression in more severe Crohn's disease patients, Interestingly, a recent study demonstrated that the colonic CD90 + stromal cells from Crohn's disease patients presented significantly lower PD-L1, together with reduced capacity to suppress Th1 inflammation. 26 Reduction of the PD-1/PD-L1 signaling thus appears to be a common mechanism through which the inflammation in Crohn's disease persists over time. A special type of Th17 cells with Th1 signature and expressing both IL-17…”