Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by IFN-gamma, TGF-beta, and cell density.
Mesenchymal stromal cells (MSC) possess immunosuppressive properties, yet when treated with IFN-gamma they acquire APC functions. To gain insight into MSC immune plasticity, we explored signaling pathways induced by IFN-gamma required for MHC class II (MHC II)-dependent Ag presentation. IFN-gamma-induced MHC II expression in mouse MSC was enhanced by high cell density or serum deprivation and suppressed by TGF-beta. This process was regulated by the activity of the type IV CIITA promoter independently of STAT1 activation and the induction of the IFN regulatory factor 1-dependent B7H1/PD-L1 encoding gene. The absence of direct correlation with the cell cycle suggested that cellular connectivity modulates IFN-gamma responsiveness for MHC II expression in mouse MSC. TGF-beta signaling in mouse MSC involved ALK5 and ALK1 TGF-beta RI, leading to the phosphorylation of Smad2/Smad3 and Smad1/Smad5/Smad8. An opposite effect was observed in human MSC where IFN-gamma-induced MHC II expression occurred at the highest levels in low-density cultures; however, TGF-beta reduced IFN-gamma-induced MHC II expression and its signaling was similar as in mouse MSC. This suggests that the IFN-gamma-induced APC features of MSC can be modulated by TGF-beta, serum factors, and cell density in vitro, although not in the same way in mouse and human MSC, via their convergent effects on CIITA expression.
Romieu-Mourez
Raphaëlle
R
Department of Medicine and Oncology, Sir Mortimer B. Davis Jewish General Hospital and Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
François
Moïra
M
Boivin
Marie-Noëlle
MN
Stagg
John
J
Galipeau
Jacques
J
D000328:Adult; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002452:Cell Count; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D006681:HLA-D Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D007371:Interferon-gamma / Q000502:physiology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
D006681:HLA-D Antigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma