Altered receptor expression and decreased sensitivity of T-cells to the stimulatory cytokines IL-2, IL-7 and IL-12 in HIV infection.

ABSTRACT

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 stimulatory cytokines IL-2, IL-7 and IL-12 in HIV-infected patients and HIV-negative controls were compared by examining their effect on the production of secondary cytokines (IFNgamma, IL-4 and IL-10), by simultaneous determination of T-cell activation and apoptosis and by measuring cytokine receptor expression. Production of IFNgamma was decreased in PBMC from the patients after stimulation with several combinations of stimulatory cytokines. IL-10 was only induced upon stimulation with IL-2 and IL-12 and tended to be produced more in patients. Expression of the different cytokine receptor chains showed complex alterations in HIV+ patients as compared to controls. The most pronounced changes were decreased expression of both IL-2Ralpha and IL-7Ralpha chain on CD8+ T-cells and an increase of IL-12Rbeta on both T-cell subsets from the patients. Evaluation of CD25 upregulation and blast formation revealed a deficient response to all three stimulatory cytokines in CD8+ but not in CD4+ T-cells from patients as compared to controls. Both CD4+ and CD8+ T-cells from the patients were less sensitive to the anti-apoptotic 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-cells, 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-cells to respond to these cytokines could contribute to the HIV-related immune dysfunction.