title: Hyperlipidemia Alters Regulatory T Cell Function and Promotes Resistance to Tolerance Induction Through Costimulatory Molecule Blockade.
abstract: Recent work from our laboratory has shown that hyperlipidemia promotes accelerated rejection of vascularized cardiac allografts in mice by inducing anti-donor Th17 reactivity and production of IL-17. Here, we show that hyperlipidemia also affects FoxP3(+) regulatory T cells (Tregs). Hyperlipidemia promotes the development of Tregs that express low levels of CD25. Hyperlipidemia also promotes a decrease in central Tregs and an increase in effector Tregs that appears to account for the increase in the frequency of CD25(low) Tregs. Alterations in Treg subsets also appear to lead to alterations in Treg function. The ability of FoxP3(+) , CD25(high) , CD4(+) Tregs from hyperlipidemic mice to inhibit proliferation of effector T cells stimulated with anti-CD3 and CD28 was reduced when compared with Tregs from control mice. Regulatory T cells isolated from hyperlipidemic recipients exhibit increased activation of Akt, and a reduction in Bim levels that permits the expansion of FoxP3(+) CD25(low) CD4(+) T cells. Hyperlipidemic mice were also resistant to tolerance induction using costimulatory molecule blockade consisting of anti-CD154 and CTLA4Ig, a strategy that requires Tregs. Together, our data suggest that hyperlipidemia profoundly affects Treg subsets and function as well as the ability to induce tolerance.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Tufts University School of Medicine, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Bagley
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Tufts University School of Medicine, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Schuster Family Transplantation Research Center Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: A
authors.initials: A
authors.lastname: Chandrakar
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Tufts University School of Medicine, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Iacomini
mesh_terms: D000069594:Abatacept / Q000737:chemistry*; D000818:Animals; D023201:CD40 Ligand / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D006949:Hyperlipidemias / Q000503:physiopathology*; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D023201:CD40 Ligand; D000069594:Abatacept
keywords: Hyperlipidemia; rejection; tolerance; tolerance: costimulation blockade