Modulation of PD-L1 and CD8 Activity in Idiopathic and Infectious Chronic Inflammatory Conditions

Abstract

Programmed death-ligand 1 (PD-L1) can reduce the immune response by inhibiting CD8 T cell proliferation and cytotoxic activity. We studied a series of human viral (molloscum, human papillomavirus, herpes simplex, cytomegalovirus, Epstein-Barr virus, smallpox) and bacterial infections (H pylori) for the in situ expression of PD L1, mononuclear cell infiltration, and CD8 activity and compared this to noninfectious idiopathic inflammatory conditions to better define which immune responses may be more highly correlated with an infectious agent. Each viral and bacterial infection showed increased PD-L1 expression that was most prominent in the mononuclear cell/CD8+ infiltrate surrounding the infection. However, the CD8 cells were mostly quiescent as evidenced by the low Ki67 index and minimal granzyme expression. Using a melanoma mouse model, acute reovirus infection increased PD L1 expression, but decreased CD8 cytotoxic activity and Treg (FOXP3) cell numbers. In comparison, idiopathic noninfectious chronic inflammatory processes including lichen sclerosis, eczema, Sjogren’s disease, and ulcerative colitis showed a comparable strong PD L1 expression in the mononuclear cell infiltrates but much greater Treg infiltration. However, this strong immunosuppressor profile was ineffective as evidenced by strong CD8 proliferation and granzyme expression. This data suggests that viral and bacterial infections induce a PD L1 response that, unlike noninfectious chronic inflammatory conditions, dampens the activity of the recruited CD8 cells which, in turn, may enhance the ability of anti-PD L1 therapy to eliminate the infectious agent.

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

“…This may underlie the PD‐L1 overexpression in these diseases, as we observed. Indeed, PD‐L1 epithelial expression has been described in a small number of IBD, 20 UC 21 and CD cases 22 . Additionally, and in line with our findings, increased PD‐L1 epithelial expression has also been described in pancreatic ductal cells of patients with type 2 autoimmune pancreatitis, a condition that is often associated with UC, and thus probably pathogenetically related 23…”

“…We believe that this mechanism may be responsible for the PD‐L1 overexpression that we observed in PD1i colitis and IBD cases. This is supported by experimental data showing a role for PD‐1‐mediated inhibitory signals in limiting enteric inflammation in IBD 20–22,29,31,32 . Interestingly, however, one of these studies yielded opposite results, with PD‐L1‐deficient mice showing increased susceptibility to experimental gut injury, an effect that appeared to be mediated by an altered gut microbiota 32 .…”

“…ICI colitis, infection and IBD show significant clinicopathological overlap, 2,4,5,24–27 and distinction is important for accurate diagnosis and optimum clinical management. The ability of some commensal segmented filamentous bacteria to induce Th17 cell accumulation in the lamina propria 28 and the ability of infectious organisms to induce PD‐L1 overexpression to promote immune evasion 21,29 could underlie the PD‐L1 epithelial overexpression observed in our cases of CMV colitis. Indeed, in human biopsies with CMV infection, PD‐L1 overexpression was observed and correlated with reduced CD8 activation and reduced infiltration of regulatory T cells (Tregs) 21 .…”

Helicobacter: Inflammation, immunology and vaccines

“…This is known to suppress CD8 + T‐cell activation and proliferation, and promote regulatory T‐cell responses. Mezache et al . showed that PD‐L1 is highly expressed in normal gastric mucosal biopsies and upregulated even further in H. pylori‐ infected tissue.…”

“…IL-22producing T cells have previously been implicated in the pathogenesis of H. pylori infection. 25 Shamsdin et al 26 Mezache et al 27 showed that PD-L1 is highly expressed in normal gastric mucosal biopsies and upregulated even further in H. pylori-infected tissue. The majority of PD-L1 + mononuclear cells were CD8 + , indicating that these cells play an important role in modulating the mucosal immune response.…”