TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+stromal cells

Ellen J. Beswick, Jameel R. Johnson, Jamal I. Saada, Martin Humen, Jenifer House, Sara Dann, Suimin Qiu, Allan R. Brasier, Don W. Powell, Victor E. Reyes, Irina V. Pinchuk

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Abstract

Signaling via programmed death ligand-1 (PD-L1) and PD-L2 is crucial for maintaining peripheral tolerance. CD90+myofibroblasts/fibroblasts (CMFs) are major programmed cell death-1 (PD-1) ligand-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. In this study, 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 TLR5 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. Copyright

Original languageEnglish (US)
Pages (from-to)2218-2229
Number of pages12
JournalJournal of Immunology
Volume193
Issue number5
DOIs
StatePublished - Sep 1 2014

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Beswick, E. J., Johnson, J. R., Saada, J. I., Humen, M., House, J., Dann, S., Qiu, S., Brasier, A. R., Powell, D. W., Reyes, V. E., & Pinchuk, I. V. (2014). TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+stromal cells. Journal of Immunology, 193(5), 2218-2229. https://doi.org/10.4049/jimmunol.1203441