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

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 vi...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2014-09, Vol.193 (5), p.2218-2229
Main Authors: Beswick, Ellen J, Johnson, Jameel R, Saada, Jamal I, Humen, Martin, House, Jenifer, Dann, Sara, Qiu, Suimin, Brasier, Allan R, Powell, Don W, Reyes, Victor E, Pinchuk, Irina V
Format: Article
Language:English
Subjects:
Animals
B7-H1 Antigen - genetics
B7-H1 Antigen - immunology
Colon - cytology
Colon - immunology
Female
Humans
Immune Tolerance - physiology
Interferon-gamma - genetics
Interferon-gamma - immunology
Intestinal Mucosa - cytology
Intestinal Mucosa - immunology
Male
Mice
Mice, Knockout
Myeloid Differentiation Factor 88 - genetics
Myeloid Differentiation Factor 88 - immunology
Myofibroblasts - cytology
Myofibroblasts - immunology
Stromal Cells - cytology
Stromal Cells - immunology
Thy-1 Antigens - genetics
Thy-1 Antigens - immunology
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - immunology
Up-Regulation - genetics
Up-Regulation - immunology
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1203441