ALTERED RECEPTOR EXPRESSION AND DECREASED SENSITIVITY OF T-CELLS TO THE STIMULATORY CYTOKINES IL-2, IL-7 AND IL-12 IN HIV-INFECTION

A dysregulated production of regulatory cytokines has been proposed as a determinant in the progression of HIV infection. The sensitivity of T-cells to these cytokines has, however, not fully been investigated. Therefore, the responses of PBMC and T-cell subsets to the stimulator y cytokines IL-2, IL-7 and IL-12 in HIV-infected patients and HIV-nega tive controls were compared by examining their effect on the productio n of secondary cytokines (IFN gamma, IL-4 and IL-10), by simultaneous determination of T-cell activation and apoptosis and by measuring cyto kine receptor expression. Production of IFN gamma was decreased in PBM C from the patients after stimulation with several combinations of sti mulatory cytokines. IL-10 was only induced upon stimulation with IL-2 and IL-12 and tended to be produced more in patients. Expression of th e different cytokine receptor chains showed complex alterations in HIV + patients as compared to controls. The most pronounced changes were d ecreased expression of both IL-2R alpha and IL-7R alpha chain on CD8T-cells and an increase of IL-12R beta on both T-cell subsets from the patients. Evaluation of CD25 upregulation and blast formation reveale d a deficient response to all three stimulatory cytokines in CD8+ but not in CD4+ T-cells from patients as compared to controls. Both CD4+ a nd CD8+ T-cells from the patients were less sensitive to the anti-apop totic effect of IL-7 whereas only CD8+ T-cells were less sensitive to the anti-apoptotic effect of IL-2. The present data show that CD8+ T-c ells, and to a lesser extent CD4+ T-cells, become less sensitive to IL -2, IL-7 and IL-12 during HIV infection. The decreased capacity of T-c ells to respond to these cytokines could contribute to the HIV-related immune dysfunction. (C) 1998 Elsevier Science B.V. All rights reserve d.