Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis.
Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100(tg)) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4(+) T cell hybridomas were MHC class II-restricted and expressed a single T cell receptor (TCR) variable (V) beta chain, TRBV31, with different Valpha chains. Immunization of huB100(tg)xLdlr(-/-) mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4(+) T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.
Hermansson
Andreas
A
Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm SE-17176, Sweden.
Ketelhuth
Daniel F J
DF
Strodthoff
Daniela
D
Wurm
Marion
M
Hansson
Emil M
EM
Nicoletti
Antonino
A
Paulsson-Berne
Gabrielle
G
Hansson
Göran K
GK
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000502:physiology; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D053299:Apolipoprotein B-100 / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular; D008077:Lipoproteins, LDL / Q000276:immunology* / Q000494:pharmacology; D008315:Malondialdehyde / Q000494:pharmacology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D053299:Apolipoprotein B-100; D008077:Lipoproteins, LDL; D008315:Malondialdehyde; D011948:Receptors, Antigen, T-Cell; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C099252:oxidized low density lipoprotein