title: TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+ stromal cells.
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.
authors: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131;
authors: Ellen J
authors: EJ
authors: Beswick
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555;
authors: Jameel R
authors: JR
authors: Johnson
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555;
authors: Jamal I
authors: JI
authors: Saada
authors: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555;
authors: Martin
authors: M
authors: Humen
authors: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555;
authors: Jenifer
authors: J
authors: House
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555;
authors: Sara
authors: S
authors: Dann
authors: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555;
authors: Suimin
authors: S
authors: Qiu
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; Institute of Translational Science, University of Texas Medical Branch, Galveston, TX 77555;
authors: Allan R
authors: AR
authors: Brasier
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; Institute of Translational Science, University of Texas Medical Branch, Galveston, TX 77555; Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555; and.
authors: Don W
authors: DW
authors: Powell
authors: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
authors: Victor E
authors: VE
authors: Reyes
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; Institute of Translational Science, University of Texas Medical Branch, Galveston, TX 77555; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555 ivpinchu@utmb.edu.
authors: Irina V
authors: IV
authors: Pinchuk
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D003106:Colon / Q000166:cytology / Q000276:immunology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D058628:Myofibroblasts / Q000166:cytology / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology; D018800:Thy-1 Antigens / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; C573415:IFNG protein, human; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D018800:Thy-1 Antigens; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma