Constitutive and Inducible Expression of B7 Family of Ligands by Human Airway Epithelial Cells

Abstract

Activated T cells have been implicated in chronic rhinosinusitis (CRS) and asthma and physically interact with epithelial cells in the airways. We now report that human airway epithelial cells display significant constitutive cell-surface expression of costimulatory ligands, B7-H1, B7-H2, B7-H3, and B7-DC. Expression of B7-H1 and B7-DC was selectively induced by stimulation of either BEAS2B or primary nasal epithelial cells (PNEC) with interferon (IFN)-gamma (100 ng/ml). The combination of IFN-gamma and tumor necrosis factor-alpha (100 ng/ml) selectively induced expression better than IFN-gamma alone. Fluticasone treatment (10(-7) M) reduced the baseline expression and inhibited the induction of B7-H1 and B7-DC in BEAS2B cells. In vitro exposure of PNEC to IFN-gamma also resulted in selective induction of B7-H1 and B7-DC. Monoclonal antibody blockade of B7-H1 or B7-DC enhanced IFN-gamma expression by purified T cells in co-culture experiments, suggesting that these two B7 homologs inhibit T cell responses at the mucosal surface. Immunohistochemical staining of human sinonasal surgical tissue confirmed the presence of B7-H1, B7-H2, and B7-H3 in the epithelial cell layer, especially in samples from patients diagnosed with Samter's Triad, a severe form of CRS. Real-time PCR analysis of sinonasal tissue revealed elevated levels of B7-H1 and B7-DC in CRS compared with controls. These results demonstrate that epithelial cells express functional B7 costimulatory molecules and that expression of selected B7 family members is inducible in vitro and in vivo. Epithelial B7 homologs could play a role in regulation of lymphocytic activity at mucosal surfaces.

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

“…15,41 In our immunohistochemical analysis mean intraepithelial PD-L1+ tumor-infiltrating lymphocytes were higher in medullary carcinoma compared with microsatellite unstable and microsatellite stable colorectal carcinomas. In normal physiology, PD-L1 expression can be induced by IFNγ as a means to protect tissues from infection-induced immune-mediated damage, 42,43 but in tumors enriched with an IFNγ microenvironment, such as microsatellite unstable tumors, the same mechanism may possibly be exploited as a means of antitumor immune escape. There is also evidence that PD-L1 expression can be driven by oncogenic signaling pathways as is the case with PTEN deletion in glioblastomas 44 and constitutive anaplastic lymphoma kinase signaling in lung cancers, which drive PD-L1 expression through signal transducer and activator 3 (STAT3) signaling.…”

Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

“…Epithelial cells weakly express cell surface molecules typically associated with T cell interactions including HLA-DR, CD40, Fas and Fas ligand and most of these are induced by T cell cytokines. Epithelial cells also constitutively express costimulatory molecules, B7-H1, B7-H2, B7-H3 and B7-DC [50]. Levels of expression of B7-H1 and B7-DC are increased by exposure to T cell cytokines including IFN-γ.…”

“…Although the effect of costimulatory molecules on epithelial cells is not fully understood, expression of B7-H1 and B7-DC on epithelial cells affects T cell responses. Recent studies suggest that one important function of B7-H1 is the induction of T regulatory cells, and the strong expression of B7-H1 in activated epithelium in vivo may reflect part of a feedback inhibitory mechanism [50][51][52].…”

“…Epithelial cells also express antiinflammatory or immunosuppressive cell surface molecules including B7-H1, B7-DC, IL-13RA2 and FASL (Figure 1) [50,64,[69][70][71][72][73][74][75][76]. Many of these molecules are induced by proinflammatory cytokines and Th2 cytokines, suggesting that they may be regulated by negative feedback pathways that dampen inflammatory signaling [69,71].…”

Biomarkers of Response to Immune Modulatory Therapies in Cancer

“…Innate immune resistance refers to the constitutive expression of PD-L1 by tumour cells secondary to increased signalling via oncogenic pathways, independent of the cytokine milieu of the tumour microenvironment [75,77]. On the contrary, adaptive immune resistance is a process whereby tumour cells adapt to the endogenous immune response through aberrant upregulation of PD-L1 in the context of interferon gamma release by tumour infiltrating lymphocytes [78,79]. This mirrors the physiological role of PD-L1 upregulation, which serves to prevent excessive immune-mediated damage as a result of the immune response to infection [75,77].…”