Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.
It has been shown that mesenchymal stem cells (MSCs) induce T cells to become unresponsive. We characterized the phenotype of these T cells by dissecting the effect of MSCs on T-cell activation, proliferation, and effector function. For this purpose, an in vitro murine model was used in which T-cell responses were generated against the male HY minor histocompatibility antigen. In the presence of MSCs, the expression of early activation markers CD25 and CD69 was unaffected but interferon-gamma (IFN-gamma) production was reduced. The inhibitory effect of MSCs was directed mainly at the level of cell proliferation. Analysis of the cell cycle showed that T cells, stimulated in the presence of MSCs, were arrested at the G1 phase. At the molecular level, cyclin D2 expression was profoundly inhibited, whereas p27(kip1) was up-regulated. When MSCs were removed from the cultures and restimulated with the cognate peptide, T cells produced IFN-gamma but failed to proliferate. The addition of exogenous interleukin-2 (IL-2) did not restore proliferation. MSCs did not preferentially target any T-cell subset, and the inhibition was also extended to B cells. MSC-mediated inhibition induces an unresponsive T-cell profile that is fully consistent with that observed in division arrest anergy.
Glennie
Sarah
S
Department of Immunology and Transplantation Biology, Faculty of Medicine, Imperial College London, United Kingdom.
Soeiro
Inês
I
Dyson
Peter J
PJ
Lam
Eric W-F
EW
Dazzi
Francesco
F
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D005434:Flow Cytometry; D016193:G1 Phase / Q000276:immunology; D008213:Lymphocyte Activation; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016192:Resting Phase, Cell Cycle / Q000276:immunology
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D004247:DNA