Jian Hong1, Angela Hueckelhoven2, Lei Wang2, Anita Schmitt2, Patrick Wuchter2, Jacek Tabarkiewicz3, Christian Kleist4, Karen Bieback5, Anthony D Ho2, Michael Schmitt6. 1. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany; Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. 2. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. 3. Center for Innovative Research in Medical and Natural Sciences, Medical Faculty of University of Rzeszow, Poland. 4. Department of Transplantation Immunology, Heidelberg University Hospital, Heidelberg, Germany; Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany. 5. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 6. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: Michael.Schmitt@med.uni-heidelberg.de.
Abstract
BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) exert broad immunomodulatory functions. We recently demonstrated a strong suppressive effect of MSCs on virus-specific CD8(+) T-cell proliferation. Here, we further explored the underlying mechanism. METHODS: The role of indoleamine 2,3-dioxygenase (IDO) in inhibition of virus-specific CD8(+) T-cell proliferation by human MSCs was investigated using a mixed lymphocyte peptide culture assay, IDO intracellular staining and IDO inhibition through 1-methyl-DL-tryptophan (1-MT). Moreover, the influence of the number of passages and the seeding density of MSCs on their IDO expression and immunosuppressive ability were investigated. RESULTS: MSCs with low IDO expression exhibited a reduced suppressive effect on both allo-antigen- and cytomegalovirus (CMV)-specific CD8(+) T-cell proliferation. 1-MT could partially abrogate the suppressive effect. MSCs inhibited CMV-specific CD8(+) T-cell proliferation regardless of the number of passages and the seeding density. IDO expression of MSCs was not significantly affected by the number of passages or the seeding density. In addition, the interferon (IFN)-γ level in the culture system was crucial for MSCs to inhibit the proliferation of CMV-specific CD8(+) T cells. SUMMARY: MSCs inhibit virus-specific CD8(+) T-cell proliferation through IFN-γ-induced IDO activity, resolving current conflicting reports on this issue and indicating the potential need for prophylaxis and surveillance of virus infection in patients treated with MSCs. In addition, our study makes a contribution to the development of MSC potency assay for clinical use.
BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) exert broad immunomodulatory functions. We recently demonstrated a strong suppressive effect of MSCs on virus-specific CD8(+) T-cell proliferation. Here, we further explored the underlying mechanism. METHODS: The role of indoleamine 2,3-dioxygenase (IDO) in inhibition of virus-specific CD8(+) T-cell proliferation by human MSCs was investigated using a mixed lymphocyte peptide culture assay, IDO intracellular staining and IDO inhibition through 1-methyl-DL-tryptophan (1-MT). Moreover, the influence of the number of passages and the seeding density of MSCs on their IDO expression and immunosuppressive ability were investigated. RESULTS: MSCs with low IDO expression exhibited a reduced suppressive effect on both allo-antigen- and cytomegalovirus (CMV)-specific CD8(+) T-cell proliferation. 1-MT could partially abrogate the suppressive effect. MSCs inhibited CMV-specific CD8(+) T-cell proliferation regardless of the number of passages and the seeding density. IDO expression of MSCs was not significantly affected by the number of passages or the seeding density. In addition, the interferon (IFN)-γ level in the culture system was crucial for MSCs to inhibit the proliferation of CMV-specific CD8(+) T cells. SUMMARY: MSCs inhibit virus-specific CD8(+) T-cell proliferation through IFN-γ-induced IDO activity, resolving current conflicting reports on this issue and indicating the potential need for prophylaxis and surveillance of virus infection in patients treated with MSCs. In addition, our study makes a contribution to the development of MSC potency assay for clinical use.
Authors: Sabine Geiger; Emrah I Ozay; Ulf Geumann; Marina K Hereth; Terese Magnusson; Sudarvili Shanthalingam; Daniela Hirsch; Stefanie Kälin; Christine Günther; Barbara A Osborne; Gregory N Tew; Felix G Hermann; Lisa M Minter Journal: Mol Ther Date: 2019-05-16 Impact factor: 11.454
Authors: Ana C R Moreno; Bruna F M M Porchia; Roberta L Pagni; Patrícia da Cruz Souza; Rafael Pegoraro; Karine B Rodrigues; Tácita B Barros; Luana R de Melo Moraes Aps; Eliseu F de Araújo; Vera L G Calich; Luís C de Souza Ferreira Journal: Front Immunol Date: 2018-08-22 Impact factor: 7.561