Cardiolipin activates antigen-presenting cells via TLR2-PI3K-PKN1-AKT/p38-NF-kB signaling to prime antigen-specific naïve T cells in mice
| Autor: | Young Joo Kim, Jung Ah Cho, Tae Joo Kim, Seung Yong Seong, Hye Jung Moon, Hye Kyung Yoon |
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| Rok vydání: | 2018 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Cardiolipins CD14 Immunology Lipopolysaccharide Receptors Priming (immunology) Autoimmunity Biology Lymphocyte Activation p38 Mitogen-Activated Protein Kinases Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound Cardiolipin Animals Immunology and Allergy Antigen-presenting cell Protein Kinase C PI3K/AKT/mTOR pathway Mice Knockout NF-kappa B Dendritic Cells Antiphospholipid Syndrome Molecular biology Toll-Like Receptor 2 CD11c Antigen Mitochondria Mice Inbred C57BL TLR2 030104 developmental biology chemistry Signal transduction Proto-Oncogene Proteins c-akt CD8 Signal Transduction |
| Zdroj: | European Journal of Immunology. 48:777-790 |
| ISSN: | 0014-2980 |
| Popis: | Mitochondrial defects and antimitochondrial cardiolipin (CL) antibodies are frequently detected in autoimmune disease patients. CL from dysregulated mitochondria activates various pattern recognition receptors, such as NLRP3. However, the mechanism by which mitochondrial CL activates APCs as a damage-associated molecular pattern to prime antigen-specific naive T cells, which is crucial for T-cell-dependent anticardiolipin IgG antibody production in autoimmune diseases is unelucidated. Here, we show that CL increases the expression of costimulatory molecules in CD11c+ APCs both in vitro and in vivo. CL activates CD11c+ APCs via TLR2-PI3K-PKN1-AKT/p38MAPK-NF-κB signaling. CD11c+ APCs that have been activated by CL are sufficient to prime H-Y peptide-specific naive CD4+ T cells and OVA-specific naive CD8+ T cells. TLR2 is necessary for anti-CL IgG antibody responses in vivo. Intraperitoneal injection of CL does not activate CD11c+ APCs in CD14 KO mice to the same extent as in wild-type mice. CL binds to CD14 (Kd = 7 × 10-7 M). CD14, but not MD2, plays a role in NF-kB activation by CL, suggesting that CD14+ macrophages contribute to recognizing CL. In summary, CL activates signaling pathways in CD11c+ APCs through a mechanism similar to gram (+) bacteria and plays a crucial role in priming antigen-specific naive T cells. |
| Databáze: | OpenAIRE |
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