MSC license CD34‐DC into regulatory DC via Notch pathway activation

Abstract

In this study, we intent to clarify these mechanisms by examining the immunosuppressive effect of human adult MSC on adult DC differentiated from CD34+ hematopoietic progenitor cells (HPC). We showed that MSC halt both interstitial and Langerhans cell differentiation from adult CD34+HPC, as assessed by the decreased expression of CD1a, CD14, CD86, CD80 and CD83 antigens on their cell surface. Accordingly, the allostimulatory capacity of these CD34‐DC was impaired. Furthermore, we showed that (i) MSC inhibited commitment of CD34+HPC into immature DC, but not maturation of CD34‐DC (ii) this inhibitory effect was reversible and (iii) MSC‐DC induced the generation of allo‐Ag specific regulatory T cells following secondary allo‐stimulation. Direct coculture of MSC with CD34+HPC resulted in much stronger immunosuppressive effect and led to an activation of the Notch pathway as assessed by the overexpression of Hes1 in MSC‐DC. Finally, DAPT, a gamma‐secretase inhibitor that inhibits NOTCH signaling was able to overcome MSC‐DC defects. In conclusion, our data suggest that MSC licence adult CD34+HPC to differentiate into regulatory DC, through activation of the NOTCH pathway.