Relationship between regulatory T cells subsets and lipid profile in dyslipidemic patients: a longitudinal study during atorvastatin treatment

Abstract

BackgroundThe CD4+ T-lymphocytes and their subtype CD4 + CD25highFoxP3+ regulatory T cells are receiving growing interest as major regulators of atherogenesis. We sought to investigate 1) whether the CD4 + cell subsets were expressed differently in dyslipidemic patients (Pts) and healthy subjects (HS) and 2) whether atorvastatin treatment could be associated in-vivo and in-vitro with cell changes in expression and functional response.MethodsCD4+ subsets frequency (CD4 + CD25highFoxP3+, CD4 + CD25-FoxP3+) and mRNA expression for FoxP3, IL-10 and TGF-β were evaluated in 30 consecutive Pts at baseline and after a 3-month atorvastatin therapy, and in 17 HS.ResultsThe % of CD4 + cells did not differ between HS and Pts. The % of CD4 + CD25highFoxP3+ was higher in Pts than HS and did not change during treatment. The CD4 + CD25-FoxP3+ cells were similar between the two groups and were lower in Pts at visit 2. Cytokine expression and FoxP3 did not differ in HS and Pts and no substantial change was observed during treatment. At visit 1, CD4 + CD25highFoxP3+ cells were significantly correlated with both total-cholesterol (r = 0.570, P = 0.0002), LDL-cholesterol (r = 0.715, P = 0.0001), Apolipoprotein B (r = 0.590, P = 0.0001). In-vitro atorvastatin (up to 5 μM) failed to induce any significant modulation of cell functions.ConclusionCD4 + CD25highFoxP3+ regulatory cells seem to be over-stimulated in the early pre-clinical phase of atherosclerosis and a relationship exists between their frequency and circulating lipids. A potential immuno-modulation by statin treatment is not achieved through a normalization in peripheral CD4 + cell subsets.

High concentrations of atorvastatin reducein-vitrofunction of conventional T and regulatory T cells

“…In line with these findings, previous reports have observed a down-regulation of functional markers such as CTLA-4, the inducible co-stimulator (ICOS) and the glucocorticoid-induced TNFR-related protein (GITR) on murine T regs pretreated with ATV, lovastatin or simvastatin at concentrations ≥ 2 μM [33,39] as well as FoxP3 expression on CD4 + CD25 + cells treated in vitro with 10 µM ATV [37], highlighting the relevance of the mevalonate pathway co-ordinating T reg functions. However, this feature was lost when they were cultured with the highest ATV concentration as a reduction of these molecules was observed.…”

“…This could be problematic, especially when the proliferative response is evaluated through [ 3 H]-thymidine incorporation, which does not particularly distinguish the proliferating cell population [35]. Although we used supratherapeutic ATV concentrations (1 μM), this did not affect T reg suppressive function, which was similar to the effect of 0·001 μM ATV [37], a similar concentration to that found in individuals taking low-dose statins [38]. Moreover, others have demonstrated higher T reg suppressive capacity in the presence of high concentrations of statins in vitro (25 µM) [32]; however, these concentrations could affect also cell viability [37].…”

“…In other studies, human T regs were obtained as CD4 + CD25 + T cells, which might not represent true T regs ; therefore, activated T cons could proliferate in the presence of strong stimulation, masking the suppression activity of T regs [15,34]. Moreover, others have demonstrated higher T reg suppressive capacity in the presence of high concentrations of statins in vitro (25 µM) [32]; however, these concentrations could affect also cell viability [37]. Similarly, contradictory results could be derived from the type of statin used, considering the lipophilic or hydrophilic nature of these drugs, that could facilitate or block its spread across the cell membrane [36].…”

“…Similarly, contradictory results could be derived from the type of statin used, considering the lipophilic or hydrophilic nature of these drugs, that could facilitate or block its spread across the cell membrane [36]. Moreover, others have demonstrated higher T reg suppressive capacity in the presence of high concentrations of statins in vitro (25 µM) [32]; however, these concentrations could affect also cell viability [37]. Although we used supratherapeutic ATV concentrations (1 μM), this did not affect T reg suppressive function, which was similar to the effect of 0·001 μM ATV [37], a similar concentration to that found in individuals taking low-dose statins [38].…”

“…Moreover, others have demonstrated higher T reg suppressive capacity in the presence of high concentrations of statins in vitro (25 µM) [32]; however, these concentrations could affect also cell viability [37]. Although we used supratherapeutic ATV concentrations (1 μM), this did not affect T reg suppressive function, which was similar to the effect of 0·001 μM ATV [37], a similar concentration to that found in individuals taking low-dose statins [38]. Similar to our findings, pretreatment with simvastatin at 2 μM or ATV or lovastatin at 5 μM impaired T reg suppressive capability in mice, as evaluated by the [ 3 H]-thymidine assay [33], highlighting the relevance of the mevalonate pathway in coordinating T reg functions.…”