IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis
During atherogenesis, LDL is oxidized, generating various oxidation-specific neoepitopes, such as malondialdehyde-modified (MDA-modified) LDL (MDA-LDL) or the phosphorylcholine (PC) headgroup of oxidized phospholipids (OxPLs).These epitopes are recognized by both adaptive T cell-dependent (TD) and innate T cell-independent type 2 (TI-2) immune responses.We previously showed that immunization of mice with MDA-LDL induces a TD response and atheroprotection.In addition, a PC-based immunization strategy that leads to a TI-2 expansion of innate B-1 cells and secretion of T15/EO6 clonotype natural IgM antibodies, which bind the PC of OxPLs within oxidized LDL (OxLDL), also reduces atherogenesis.T15/EO6 antibodies inhibit OxLDL uptake by macrophages.We now report that immunization with MDA-LDL, which does not contain OxPL, unexpectedly led to the expansion of T15/EO6 antibodies.MDA-LDL immunization caused a preferential expansion of MDA-LDL-specific Th2 cells that prominently secreted IL-5.In turn, IL-5 provided noncognate stimulation to innate B-1 cells, leading to increased secretion of T15/EO6 IgM.Using a bone marrow transplant model, we also demonstrated that IL-5 deficiency led to decreased titers of T15/EO6 and accelerated atherosclerosis.Thus, IL-5 links adaptive and natural immunity specific to epitopes of OxLDL and protects from atherosclerosis, in part by stimulating the expansion of atheroprotective natural IgM specific for OxLDL.Nonstandard abbreviations used: alkaline phosphatase (AP); bone marrow transplantation (BMT); fast-performance liquid chromatography (FPLC); immune complex (IC); LDL receptor (LDLR); malondialdehyde (MDA); MDA-modified LDL (MDA-LDL); oxidized LDL (OxLDL); oxidized phospholipid (OxPL); 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC); phosphorylcholine (PC); relative light units (RLU); T cell-dependent (TD); T cell-independent (TI); T cellindependent type 2 (TI-2).