Abstract
The 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. Tissues and cells derived from Crohn's disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture. A 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. We 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.
Highlights
Dysregulation of T helper (Th) cell responses in inflammatory bowel disease (IBD) is critically involved in colonic tissue damage
A similar observation was made using in situ analysis: programmed death-ligand 1 (PD-L1) protein was mostly upregulated in both ulcerative colitis (UC) mucosal lamina propria (LP) and to a less extent in epithelium but decreased in Crohn’s disease (CD) LP compared to the healthy controls (Figure 1B)
Analysis of colonic tissue obtained from surgical levels in UC and CD colonic mucosa were compared to normal tissue controls obtained from healthy individuals
Summary
Dysregulation of T helper (Th) cell responses in inflammatory bowel disease (IBD) is critically involved in colonic tissue damage. For ulcerative colitis (UC) colonic mucosal production of IFN-γ is either suppressed or comparable to normal tissue with an increase in Th2 cytokines IL-5 and IL-13 [2,3,4] While this disruption of balanced Th1/Th2 cell responses is among the important effector mechanisms contributing to the IBD pathophysiology, the mechanisms responsible for this dysregulation remain unclear. Abnormities in PD-L1 and PD-L2 expression/signaling contribute to several chronic infectious and inflammatory diseases, such as type 1 diabetes, rheumatoid arthritis, allergy, and chronic obstructive pulmonary disease In these diseases, alterations in the expression and signaling of PD-1 and its ligands result in the dysregulation of Th1/Th2 responses and overall IFNγ production [11,12,13,14,15]. 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
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