Immune mechanisms in atherosclerosis : the role of T cells in murine models of atherosclerosis

Abstract

Atherosclerosis is an inflammatory disease. Much interest has been focused on the immune responses in the pathogenesis of the disease. The role of T cells in the development of atherosclerosis was therefore investigated in murine models in this study.

The project started with the finding that immunocompetent cells infiltrated into all phases of atherosclerotic lesions in hypercholesterolemic apoE knockout (E-/-) mice with a dominance of CD4+ T cells appearing in clusters. Analyses of their T cell receptors indicated that V[beta]6+ T cells were present in all lesions, and V[beta]5.2+, V[beta]16+ and V[alpha]34s+ were present in the majority of the lesions. As in man, Th1 cells were the dominant T cells in E-/- mice. However, severe hypercholesterolemia induced by high fat diet led to a switch of Th1 to Th2/Th3-dependent immune responses, paralleled by increased IL-4 and TGF-[beta] and decreased IFN-[gamma] expressions in the lesions, lymphoid organs and blood. The switch was further evidenced by the shift of IgG2a to IgG1 and IgG2b antibodies to oxLDL. Similar changes were also detected in hypercholesterolemic mice treated with poloxamer-407. A new murine model was generated by crossbreeding E-/- mice with severe combined immunodeficient mice (SCID, S-/-) to further explore the role of adaptive immunity in atherosclerosis. A significant reduction of lesion formation was found in E-/-S-/- mice compared with E-/-S+/+ ones. The disease was worsened dramatically in E-/-S-/- after transfer of CD4+ T cells, which was paralleled by increased IFN-[gamma] levels in plasma. Immunization with either homologous plaque homogenates or MDA-LDL reduced lesions significantly in E-/- mice. The protection was associated with elevation of IgG antibodies against both MDA-LDL and oxidized phospholipids.

In summary, our data provide a direct link between hypercholesterolemia and local immune responses in murine atherosclerosis. A strongly skewed pattern of the complementarity determining region 3 (CDR3) was indicative of oligoclonal expansions of T cells in the plaques and suggestive of antigen-driven T cell proliferation in the lesions. T and B cells cooperate in the autoimmune response to oxLDL and a link has been identified between cholesterol metabolism and the activation of Th cells in lymphoid organs and atherosclerotic lesions. Adoptive transfer of CD4+ T cells into E-/-S-/- accelerates atherosclerosis. This effect on the lesions is paralleled by increased IFN-[gamma] levels suggesting that Th1-type CD4 cells contribute a proatherogenic T-cell subset. Finally, the protective effect of immunization with oxLDL involves T cell-dependent specific IgG antibody responses.