Stearic acid is toxic for T lymphocytes in vitro but has little effect on B lymphocytes. To investigate the molecular basis for this difference, purified murine T and B lymphocytes were compared for their abilities to incorporate and metabolize stearic acid. Unstimulated T and B cells incorporated identical amounts of stearic acid into six different phospholipids and four neutral lipids. After mitogen stimulation, fatty acid uptake was increased in both lymphocyte types, but cell-specific differences were seen in the distribution of stearic acid among the various cellular lipids. Doses of stearic acid that selectively inhibited T-cell proliferation resulted in a 5-fold greater accumulation of distearoylphosphatidylcholine in T cells than in B cells. Whereas T cells did not desaturate the exogenously derived stearic acid, up to 25% of the saturated fatty acid was converted to oleic acid in B cells. These findings suggested a deficiency of stearoyl-CoA desaturase (acyl-CoA, hydrogen-donor:oxygen oxidoreductase, EC 1.14.99.5) activity in T cells, which was confirmed by subsequent studies. Cell-free extracts from B cells displayed nearly 20-fold more stearoylCoA desaturase activity than T-cell extracts, and the level of stearoyl-CoA desaturase mRNA was 30-fold higher in B cells. Collectively, our data indicate that murine T cells are deficient in unsaturated fatty acid synthesis. The deficiency of stearoylCoA desaturase in T cells may represent the basis for the differing sensitivities of T and B lymphocytes to inhibition by saturated fatty acids.Saturated and unsaturated fatty acids markedly affect lymphocyte function both in vivo and in vitro (for review, see refs. 1-3). In general, saturated fatty acids and high levels (>20 AuM) of unsaturated fatty acids are inhibitory, whereas low amounts (<10 ,M) of unsaturated fatty acids enhance lymphocyte growth and function (4-8). The mechanisms by which fatty acids alter lymphocyte function are not fully understood. Polyunsaturated fatty acids are converted to various icosanoids having potent immunopharmacological properties (9, 10). By contrast saturated and monounsaturated fatty acids have been proposed to act by changing the organization or physical properties of immune cell membranes, although this remains controversial (3, 10, 11).In studies carried out in vivo (3, 12, 13) and in vitro (8, 14), fatty acids have been shown to have a greater effect on T cells and cell-mediated immunity than on B cells and humoral immunity. For example, using highly purified murine T and B lymphocytes, we showed that stearic acid potently inhibited T-cell proliferation but had much less effect on B-cell proliferation (8). At the same concentration (50AM), oleic acid was without effect; however, when added simultaneously with stearic acid, oleic acid could obviate the inhibitory effects of the saturated fatty acid (8,15 For analysis of molecular species, radiolabeled phosphatidylcholine fractions were converted to diacylglycerides by phospholipase C digestion (19) followed by ben...