Inhibition by membrane-bound low-density lipoproteins of the primary inductive events of mitogen-stimulated lymphocyte activation.

Low-density lipoproteins (LDL) inhibit phytohemagglutinin (PHA)-enhanced accumulation of calcium ion and cyclic guanosine 3':5'-monophosphate, and phosphatidylinositol turnover in human lymphocytes. Inhibition by LDL of PHA-induced 32P incorporation into monophosphoinositide and cyclic guanosine 3':5'-monophosphate accumulation correlates directly with inhibition by LDL of calcium ion accumulation. These results suggest that calcium ion accumulation is required for PHA to direct turnover of monophosphoinositide and cyclic guanosine 3':5'-monophosphate synthesis in lymphocytes and that inhibition of this mitogen-induced response by LDL may be a direct consequence of the ability of these lipoproteins to prevent calcium ion accumulation by the activated cells. The ability of LDL to suppress PHA-enhanced calcium ion accumulation is directly proportional to the amount of LDL localized at the cell surface, indicating that internalization of the lipoproteins is not required for immunoregulation. This conclusion is supported by two additional lines of evidence: (a) LDL depleted of the bioregulatory constituent cholesterol are as effective as are native LDL in suppressing lymphocyte response to PHA; and (b) LDL-Sepharose complexes which cannot be endocytosed by the cells are as immunosuppressive as soluble LDL. The data clearly establish that membrane-bound LDL may have a regulatory role.