INKT CELLS IN DISLIPIDEMIA.

Natural killer T cells (NKT) are T lymphocytes with a reactivity directed against glycolipid antigens presented by MHC-like CD1d molecules expressed by antigen presenting cells (APC). A large proportion of these cells (invariant NKT cells (iNKT)) possess strong immunomodulatory properties which impose a profound impact on the development and course of chronic diseases. The main aim of this project was to characterize iNKT cells and CD4+ iNKT subset numerically and functionally in the context of familial hypercholesterolemia (FH) and in murine models of dyslipidemia. Additionally, using an in vitro PBMC proliferation essay in the presence of iNKT cell antigen (α-GalCer) and IL-2, we investigated how lipoproteins affect the ability of iNKT cells to proliferate following α-GalCer stimulation. We report that FH patients exhibit a significantly decreased percentage of CD4 positive iNKT compared to age and sex matched controls (Control: 40.8% ± 4.2% (±SEM), N=31; FH patients: 19.2% ± 3.5% of total iNKT (±SEM); N=26; *P<0.01), while the total numbers of iNKT cells are similar between FH patients and control individuals. iNKT cell function measured as the ability of iNKT cells to proliferate in vitro upon α-GalCer stimulation was decreased in FH patients (~ 2 fold). iNKT cells levels are decreased in the liver of LDLR -/-, ApoE-/- and ApoA-I-/- mice, but increased in the blood of LDLR -/- and ApoE-/- mice (compared to WT mice). Additionally we report that iNKT cells are enriched in cardiac lymph nodes. In vitro experiments showed that the absence of lipoproteins abrogated iNKT cell proliferation in PBMC proliferation essay in presence of α-GalCer. Finally, our data indicate that HDL is the major lipoprotein class which supports α-GalCer exposure to APCs and subsequent iNKT cell presentation under physiological conditions.