INHIBITORY EFFECTS OF VARIOUS OXYGENATED STEROLS ON THE DIFFERENTIATION AND FUNCTION OF TUMOR-SPECIFIC CYTOTOXIC T LYMPHOCYTES

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Abstract
Irradiation of skin with ultraviolet light (UVL) is capable of causing many biological and biochemical changes in this complex organ. One early consequence is the oxidation of epidermal plasma membrane cholesterol, causing the induction of a wide variety of photo-products. It is well recognized that some oxygenated sterols possess potent biological activity on mammalian cells by their ability to inhibit endogeneous mevalonate and cholesterol biosynthesis. In the few immunological systems that have been studied, there is general agreement that lymphocyte function is altered in the presence of certain oxygenated sterols. Insight into the biochemical basis for altered lymphocyte function is lacking, as both afferent and efferent blockades have been suggested. These studies were undertaken to determine the effect of various oxygenated sterols (representing a number of known cholesterol-derived photoproducts) on the generation (afferent) and function (efferent) of cytotoxic T lymphocytes (CTLs). Cell-mediated immune responses which result in the generation of both alloantigen-specific and syngeneic tumor-specific CTLs were evaluated. The results of our studies established the following points: (1) the afferent phase of an immune respone is particularly sensitive to the effects of some cholesterol photoproducts while other oxidized sterol derivatives, known to exist in skin following UVL exposure, have minimal influence on the generation of CTL responses; (2) the only known carcinogenic photoproduct of cholesterol (cholesterol α-oxide) is a very weak inhibitor of lymphocyte function; (3) presentation of oxygenated sterols via liposome membranes is 10-fold more effective than their administration in soluble form; (4) 25-hydroxycholesterol and 20α-hydroxycholesterol were found to be the most potent inhibitors, causing a parallel depression in lymphocyte proliferation, CTL activity, and endogeneous sterol biosynthesis, and (5) 7β-and 7α-hydroxycholesterol functioned in a unique manner, causing an abrogation of CTL activity without depressing proliferative responses and endogeneous sterol biosynthesis to a significant degree. These studies represent the first time that an attempt has been made to evaluate a possible biochemical basis for immune suppression known to precede experimental UVL carcinogenesis. Our results suggest that some, but not all, of the oxidation products of cholesterol found in skin following UVL irradiation exert an influence on immune responses. Derivatives of cholesterol could be partially responsible for the alterations in immunological potential of the UVL-exposed host. The induced presence of an inhibitor of CTL differentiation or function at a time following UVL tumor emergence may play a role in this process by providing an early tumor escape mechanism.

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