The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells
Abstract Background . CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Si...
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BMC
2024-11-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-024-03980-1 |
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| author | Loic Vaillant Waseem Akhter Jean Nakhle Matthieu Simon Martin Villalba Christian Jorgensen Marie-Luce Vignais Javier Hernandez |
| author_facet | Loic Vaillant Waseem Akhter Jean Nakhle Matthieu Simon Martin Villalba Christian Jorgensen Marie-Luce Vignais Javier Hernandez |
| author_sort | Loic Vaillant |
| collection | DOAJ |
| description | Abstract Background . CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8+ responses is unknown. Methods and results . We have utilized CD8+ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8+ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8+ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8+ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8+ T cells. Conclusion . In this report we showed that MSCs are able to interact with CD8+ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8+ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8+ T cells. |
| format | Article |
| id | doaj-art-3fbbf7d8d6cb4553818e55ee8beab49b |
| institution | DOAJ |
| issn | 1757-6512 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-3fbbf7d8d6cb4553818e55ee8beab49b2025-08-20T02:50:05ZengBMCStem Cell Research & Therapy1757-65122024-11-0115111410.1186/s13287-024-03980-1The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cellsLoic Vaillant0Waseem Akhter1Jean Nakhle2Matthieu Simon3Martin Villalba4Christian Jorgensen5Marie-Luce Vignais6Javier Hernandez7Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183Abstract Background . CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8+ responses is unknown. Methods and results . We have utilized CD8+ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8+ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8+ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8+ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8+ T cells. Conclusion . In this report we showed that MSCs are able to interact with CD8+ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8+ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8+ T cells.https://doi.org/10.1186/s13287-024-03980-1Mesenchymal stem/stromal cellsCD8+ T cellsMitochondrial transferImmunotherapyAutoimmunity |
| spellingShingle | Loic Vaillant Waseem Akhter Jean Nakhle Matthieu Simon Martin Villalba Christian Jorgensen Marie-Luce Vignais Javier Hernandez The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells Stem Cell Research & Therapy Mesenchymal stem/stromal cells CD8+ T cells Mitochondrial transfer Immunotherapy Autoimmunity |
| title | The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells |
| title_full | The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells |
| title_fullStr | The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells |
| title_full_unstemmed | The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells |
| title_short | The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells |
| title_sort | role of mitochondrial transfer in the suppression of cd8 t cell responses by mesenchymal stem cells |
| topic | Mesenchymal stem/stromal cells CD8+ T cells Mitochondrial transfer Immunotherapy Autoimmunity |
| url | https://doi.org/10.1186/s13287-024-03980-1 |
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