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- W2774668850 abstract "Mitochondria evolved from a symbiotic relationship between aerobic bacteria and eukaryotic cells. Consequently, mitochondrial DNA (mtDNA) represent an endogenous source of unmethylated CpG that has the potential to activate the innate immune system. In the setting of hematopoietic stem cell transplantation (HSCT), bone marrow conditioning regimens cause cell damage that can release mtDNA and lead to the subsequent activation of host antigen presenting cells, promoting the process of graft-vs-host disease. Here we demonstrate that mtDNA can activate DCs and enhance allogeneic T cell activation by TLR9- and MyD88-dependent pathways. Methods: Endotoxin-free mitochondrial oligodeoxyribonucleotides (mtODN) were synthesized and made nuclease resistant using phosphothiorate bonds. Bone marrow-derived dendritic cells (BM-DCs) from WT, TLR9-/- and MyD88-/- mice were incubated with mtODN and assayed for CD40 and CD86 upregulation by FACS, and the expression of IL-6, MCP-1 and TNF-alpha was measured by cytometric bead assay. Quantification of DC IRF-3, IRF-7 and NF-kB expression and serum mtDNA concentration following HSCT was assessed by q-PCR. Proliferation, CD69 expression and IFN-gamma production of alloreactive T cells was assessed using CD4+ T cells from 4C allospecific T cell receptor transgenic mice. Results: Serum levels of mtDNA were elevated in murine models of allogeneic-HSCT. BM-DCs were highly activated by mtODNs, demonstrating increased expression of cell-surface activation markers and inflammatory cytokines. mtODN treatment also lead to increased IRF-7 expression in a dose dependent manner, but not IRF-3 or NF-kB. These responses were abrogated in the absence of TLR9 or MyD88, indicating participation of these innate immune activation pathways. Co-incubation of BM-DCs and alloreactive CD4+ T cells demonstrated that mtODN increases alloreactive T cell activation and proliferation. Conclusions: This study demonstrates that mtDNA sequences can serve as potent activators of alloreactive T cells through their activation of DCs through innate immune pathways. These results indicate that cell injury occurring in the setting of transplantation may augment the alloimmune response through the release of endogenous mtDNA." @default.
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- W2774668850 date "2014-07-01" @default.
- W2774668850 modified "2023-10-14" @default.
- W2774668850 title "Mitochondrial DNA Can Function as an Endogenous Innate Immune Activator of Alloreactive T Cells." @default.
- W2774668850 doi "https://doi.org/10.1097/00007890-201407151-01029" @default.
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