TLR4 Activation Enhances the PD-L1–Mediated Tolerogenic Capacity of Colonic CD90+ Stromal Cells

Abstract

Signaling via Programmed Death Ligand (PD-L)-1 and PD-L2 is crucial for maintaining peripheral tolerance. CD90+ myofibroblasts/fibroblasts (CMFs) are major PD-1 ligands -expressing cells in normal human colonic mucosa. CMFs suppress activated CD4+ T cell proliferation via PD-1 ligands. It is not known whether signaling through TLRs contribute to the regulation PD-1 ligands on CMFs upon colonic mucosal tolerance. Herein, we demonstrated that stimulation of TLR4 on human CMFs upregulates PD-L1, but not PD-L2, and reinforces CMF-mediated suppression of CD4+ T cell proliferation and IFN-γ production. TLR4-mediated upregulation of PD-L1 on CMFs involved NF-κB pathways and was JAK2- and MyD88-dependent. MyD88-dependent stimulation of TLR1/2 and TLR 5 also upregulated PD-L1 expression on CMFs in culture. PD-L1 expression was drastically decreased in vivo in the colonic mucosa of mice devoid of MyD88. Induction of MyD88 deficiency in CMFs in fibroblast-specific MyD88 conditional knockout mice resulted in a strong increase in a mucosal IFN-γ expression concomitantly with the abrogation of PD-L1 expression in CMFs under homeostasis and epithelial injury induced by dextran sodium sulfate. Together these data suggest that MyD88-dependent TLR stimulation of CMFs in the normal colonic mucosa may reinforce these cells' anti-inflammatory capacity, and thus contribute to the maintenance of mucosal tolerance.

Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment

“…However, endogenous DAMP responses may not always mirror those observed to commercially available TLR ligands, as we observed no TAS response to the recombinant TLR4 ligands, HMGB1 and β-defensin 2. Similar to our findings in PC, TLR4 activation in colonic stromal cells also induced T cell suppression via increased PDL1 expression (39). TLR4 expression in PC specimens has been shown to correlate with more aggressive disease (40) and it has been previously demonstrated that LPS-induced TLR4 signaling could be a trigger in the initiation and progression of PC (41).…”

TLR4‐induced B7‐H1 on keratinocytes negatively regulates CD4+ T cells and CD8+ T cells responses in oral lichen planus

“…TLR4‐mediated upregulation of B7‐H1 on CD90 + myofibroblasts/fibroblasts in normal human colonic mucosa, through NF‐κB pathways, reinforced suppression of T‐cell reaction, thus conducing to the maintenance of mucosal tolerance . Besides, in human monocytes, NF‐κB activated by TLR4 signalling may regulate transcription of B7‐H1 via binding to one of the NF‐κB binding sites (nt −610 to −601) in the human B7‐H1 promoter .…”

“…Keratinocytes can participate and modulate inflammatory and immune responses in OLP and cause exacerbation and perpetuation of OLP . TLR4 signalling plays a critical dual role in the maintenance of immune balance including both activation and inhibition through a negative loop to avoid detrimental and inappropriate inflammatory responses . Upregulated TLR4 on epithelial cells and increased Gram‐negative bacteria have been observed in OLP sites, suggesting Gram‐negative bacteria LPS can active and enhance TLR4 signalling, thereby resulting in a series of inflammatory reaction in OLP .…”

The oncostatin M‐stromal cell axis in health and disease

“…iSCs are prodigious producers of cytokines and chemokines, and it is highly likely that immunological signals (either inflammatory or homoeostatic) may also be imprinted in iSCs . iSCs are known to interact directly with several subsets of haematopoietic immune cells in the intestine and may play a role in maintaining T cell tolerance at steady state . Furthermore, stromal cell signatures are known to correlate with poor therapeutic response in colorectal cancer, although it is not clear whether this results from stromal cell suppression of protective T cell responses, as seen in other tumour types …”