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-Grice, Suimin Qiu, Allan R. Brasier, Don W. Powell, Victor Reyes, Iryna Pinchuk

Research output: Contribution to journalArticle

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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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Myofibroblasts
Stromal Cells
Fibroblasts
Ligands
Mucous Membrane
Cell Death
Programmed Cell Death 1 Ligand 2 Protein
Up-Regulation
Cell Proliferation
Peripheral Tolerance
T-Lymphocytes
Dextran Sulfate
Knockout Mice
Homeostasis
Anti-Inflammatory Agents
Maintenance

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Beswick, E. J., Johnson, J. R., Saada, J. I., Humen, M., House, J., Dann-Grice, S., ... Pinchuk, I. (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

TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+stromal cells. / Beswick, Ellen J.; Johnson, Jameel R.; Saada, Jamal I.; Humen, Martin; House, Jenifer; Dann-Grice, Sara; Qiu, Suimin; Brasier, Allan R.; Powell, Don W.; Reyes, Victor; Pinchuk, Iryna.

In: Journal of Immunology, Vol. 193, No. 5, 01.09.2014, p. 2218-2229.

Research output: Contribution to journalArticle

Beswick, EJ, Johnson, JR, Saada, JI, Humen, M, House, J, Dann-Grice, S, Qiu, S, Brasier, AR, Powell, DW, Reyes, V & Pinchuk, I 2014, 'TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+stromal cells', Journal of Immunology, vol. 193, no. 5, pp. 2218-2229. https://doi.org/10.4049/jimmunol.1203441
Beswick, Ellen J. ; Johnson, Jameel R. ; Saada, Jamal I. ; Humen, Martin ; House, Jenifer ; Dann-Grice, Sara ; Qiu, Suimin ; Brasier, Allan R. ; Powell, Don W. ; Reyes, Victor ; Pinchuk, Iryna. / TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+stromal cells. In: Journal of Immunology. 2014 ; Vol. 193, No. 5. pp. 2218-2229.
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AU - Dann-Grice, Sara

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