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Am J Transplant. 2015 Sep;15(9):2324-35. doi: 10.1111/ajt.13351. Epub 2015 Jun 16.

Hyperlipidemia Alters Regulatory T Cell Function and Promotes Resistance to Tolerance Induction Through Costimulatory Molecule Blockade.

Author information

1
Department of Developmental, Molecular and Chemical Biology, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Tufts University School of Medicine, Boston, MA.
2
Schuster Family Transplantation Research Center Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

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.

KEYWORDS:

Hyperlipidemia; rejection; tolerance; tolerance: costimulation blockade

PMID:
26079467
PMCID:
PMC5125018
DOI:
10.1111/ajt.13351
[Indexed for MEDLINE]
Free PMC Article

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