Cardiolipin activates antigen-presenting cells via TLR2-PI3K-PKN1-AKT/p38-NF-kB signaling to prime antigen-specific naïve T cells in mice.
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 naïve 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 naïve CD4+ T cells and OVA-specific naïve 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 naïve T cells.
['Cho|Jung-Ah|JA|', 'Kim|Tae-Joo|TJ|0000-0002-3266-9716', 'Moon|Hye-Jung|HJ|', 'Kim|Young-Joo|YJ|', 'Yoon|Hye-Kyung|HK|', 'Seong|Seung-Yong|SY|0000-0002-3671-1029']
D000818:Animals D016736:Antiphospholipid Syndrome D015551:Autoimmunity D039521:CD11c Antigen D015496:CD4-Positive T-Lymphocytes D002308:Cardiolipins D003713:Dendritic Cells D018950:Lipopolysaccharide Receptors D008213:Lymphocyte Activation D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008928:Mitochondria D016328:NF-kappa B D019869:Phosphatidylinositol 3-Kinases D011493:Protein Kinase C D051057:Proto-Oncogene Proteins c-akt D015398:Signal Transduction D051195:Toll-Like Receptor 2 D048051:p38 Mitogen-Activated Protein Kinases
Cardiolipin CD11c+ APCs CD14+ macrophage Antiphospholipid syndrome PRRs