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Regulation of MHC Class II Expression and Antigen Processing in Murine and Human Mesenchymal Stromal Cells by IFN-, TGF-, and Cell Density¹

Department of Medicine and Oncology, Sir Mortimer B. Davis Jewish General Hospital and Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada

Mesenchymal stromal cells (MSC) possess immunosuppressive properties, yet when treated with IFN- they acquire APC functions. To gain insight into MSC immune plasticity, we explored signaling pathways induced by IFN- required for MHC class II (MHC II)-dependent Ag presentation. IFN--induced MHC II expression in mouse MSC was enhanced by high cell density or serum deprivation and suppressed by TGF-. 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- responsiveness for MHC II expression in mouse MSC. TGF- signaling in mouse MSC involved ALK5 and ALK1 TGF-RI, leading to the phosphorylation of Smad2/Smad3 and Smad1/Smad5/Smad8. An opposite effect was observed in human MSC where IFN--induced MHC II expression occurred at the highest levels in low-density cultures; however, TGF- reduced IFN--induced MHC II expression and its signaling was similar as in mouse MSC. This suggests that the IFN--induced APC features of MSC can be modulated by TGF-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by grants from Canadian Institutes of Health Research (MOP-15017), the Fond de Recherche en Santé du Québec, and the Canadian Stem Cell Network.

² R.R.-M. and M.F. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jacques Galipeau, Department of Medicine and Oncology, Sir Mortimer B. Davis Jewish General Hospital and Lady Davis Institute for Medical Research, McGill University, 3755 Cote Sainte-Catherine Road, Montreal, Quebec, Canada. E-mail address: jacques.galipeau{at}mcgill.ca

⁴ Abbreviations used in this paper: MSC, mesenchymal stem cell (mesenchymal stromal cell); MHC I, MHC class I; MHC II, MHC class II; GVHD, graft-versus-host disease; Pen/Strep, penicillin/streptomycin; PFA, paraformaldehyde; recombinant human; rm, recombinant mouse; DC, dendritic cell; WCE, whole cell extract; RS-MSC, rapidly self-renewing MSC; SR-MSC, slowly renewing MSC; alloBMT, allogeneic bone marrow transplantation.

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The JI 2007 179: 1411-1412. [Full Text]  

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