Modulation of human lymphocyte responses by low density lipoproteins (LDL): enhancement but not immunosuppression is mediated by LDL receptors.
The role of low density lipoprotein (LDL) receptors in mediating the immunomodulatory effects of LDL was examined by comparing responses of normal lymphocytes with those obtained from a patient with familial hypercholesterolemia (FH) lacking receptors for LDL. The function of LDL receptors in supporting lymphocyte growth was demonstrated by blocking endogenous sterol synthesis with mevinolin, a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and culturing cells in lipoprotein-deficient medium with supplemental LDL as the only source of cholesterol. Mevinolin inhibited mitogen-induced proliferation of normal and FH lymphocytes. Whereas inhibition was overcome by mevalonate, the product of the inhibited enzyme, low concentrations of LDL (less than 10 micrograms of protein/ml) restored the responses of normal but not FH lymphocytes. When normal and FH lymphocytes were cultured in the absence of mevinolin, high concentrations of LDL (greater than 100 micrograms of protein/ml) inhibited mitogen-induced lymphocyte proliferation. The inhibitory effects on normal and FH lymphocytes were similar in that both required comparably large concentrations of LDL and could be completely reversed by transferrin. When normal lymphocytes were cultured in serum-free medium supplemented with transferrin, low concentrations of LDL (less than 10 micrograms of protein/ml) caused marked augmentation of proliferation. By contrast, no enhancement of FH lymphocyte growth was observed. These results indicate that LDL-mediated enhancement of lymphocyte growth in the presence or absence of endogenous sterol biosynthesis involves specific receptors for LDL whereas the immunosuppression caused by LDL is independent of these receptors. Moreover, the results suggest that peripheral lymphocytes can be used to evaluate the functional integrity of the receptor-mediated uptake of LDL.