Bone marrow (BM)-derived Mesenchymal Stem Cells (MSC) can induce tolerance in T lymphocytes suggesting their employment to facilitate BM engraftment reducing also graft versus host disease. Thus, it is relevant to analyse the interaction of host cells with MSC in order to plan appropriate trials for their infusion. Among the lymphocyte subsets present within the BM, natural killer (NK) cells may play a role in regulating differentiation/maturation of hematopoietic stem cells and in the defence against leukemias. To understand the functional consequences of BM-MSC/lymphocytes interaction, we analysed whether i) BM-MSC can activate, rather than inhibit, lymphocytes; ii) the cross-talk between MSC and autologous natural killer lymphocytes. We derived BM-MSC from healthy donors (n=4) or patients (n=10) suffering from acute myeloid leukemia (AML) in post-chemotherapy complete remission. BM-MSC did not express the hematopoietic markers CD34, CD45, CD14, CD133 and were positive for CD15, CD73, CD166, CD29 CD44, CD54, HLA-ABC. We found that BM-MSC trigger the production of TNF-alpha, but not of IFN-gamma, by allogeneic peripheral blood mononuclear cells (PBMC) in 3 out of 7 BM-MSC/PBMC cocultures analyzed. In these PBMC, the activation markers CD25 and CD69 were upregulated. Indeed, BM-MSC can function as good stimulators in co-culture with allogeneic PBMC. On the other hand, BM-MSC populations constitutively produced TGF-beta and strongly inhibited (up to 90%) MLR when used as a third party. Interestingly, we noticed a strong expansion of NK and T lymphocytes expressing the C-Lectin type receptor CD94/NKG2 in MLR in the presence of BMMSC. This suggests that these cells favour the proliferation of lymphocytes bearing members of Inhibitory Receptor Superfamily (IRS). Unexpectedly, we found that autologous IL2-activated, but not freshly isolated, NK cells lysed MSC, while T lymphocytes did not kill self MSC. Binding of ICAM1 expressed by MSC to its receptor, the integrin LFA1, expressed by NK cells plays a key role in MSC/NK interaction. More importantly, NKG2D engagement by MICA or ULBP3 is responsible for the delivery of lethal hit. Conversely, HLA-I molecules do not protect MSC from NK cell-mediated injury. These data suggest that NK cells, when activated, as it may occur during the viral infections, are able to affect MSC survival, thus altering the expected therapeutic MSC-mediated effects and their nursing effect on hematopoietic stem cells.
Bone marrow-derived mesenchymal stem cells can exert both immunosuppressive and immunostimulatory effects. Regulation by autologous natural killer lymphocytes
Negrini S;
2005-01-01
Abstract
Bone marrow (BM)-derived Mesenchymal Stem Cells (MSC) can induce tolerance in T lymphocytes suggesting their employment to facilitate BM engraftment reducing also graft versus host disease. Thus, it is relevant to analyse the interaction of host cells with MSC in order to plan appropriate trials for their infusion. Among the lymphocyte subsets present within the BM, natural killer (NK) cells may play a role in regulating differentiation/maturation of hematopoietic stem cells and in the defence against leukemias. To understand the functional consequences of BM-MSC/lymphocytes interaction, we analysed whether i) BM-MSC can activate, rather than inhibit, lymphocytes; ii) the cross-talk between MSC and autologous natural killer lymphocytes. We derived BM-MSC from healthy donors (n=4) or patients (n=10) suffering from acute myeloid leukemia (AML) in post-chemotherapy complete remission. BM-MSC did not express the hematopoietic markers CD34, CD45, CD14, CD133 and were positive for CD15, CD73, CD166, CD29 CD44, CD54, HLA-ABC. We found that BM-MSC trigger the production of TNF-alpha, but not of IFN-gamma, by allogeneic peripheral blood mononuclear cells (PBMC) in 3 out of 7 BM-MSC/PBMC cocultures analyzed. In these PBMC, the activation markers CD25 and CD69 were upregulated. Indeed, BM-MSC can function as good stimulators in co-culture with allogeneic PBMC. On the other hand, BM-MSC populations constitutively produced TGF-beta and strongly inhibited (up to 90%) MLR when used as a third party. Interestingly, we noticed a strong expansion of NK and T lymphocytes expressing the C-Lectin type receptor CD94/NKG2 in MLR in the presence of BMMSC. This suggests that these cells favour the proliferation of lymphocytes bearing members of Inhibitory Receptor Superfamily (IRS). Unexpectedly, we found that autologous IL2-activated, but not freshly isolated, NK cells lysed MSC, while T lymphocytes did not kill self MSC. Binding of ICAM1 expressed by MSC to its receptor, the integrin LFA1, expressed by NK cells plays a key role in MSC/NK interaction. More importantly, NKG2D engagement by MICA or ULBP3 is responsible for the delivery of lethal hit. Conversely, HLA-I molecules do not protect MSC from NK cell-mediated injury. These data suggest that NK cells, when activated, as it may occur during the viral infections, are able to affect MSC survival, thus altering the expected therapeutic MSC-mediated effects and their nursing effect on hematopoietic stem cells.
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