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 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.
Vingerhoets
J
J
Laboratory of Immunology, Institute of Tropical Medicine, Antwerpen, Belgium. jvingerhoets@itg.be
Bisalinkumi
E
E
Penne
G
G
Colebunders
R
R
Bosmans
E
E
Kestens
L
L
Vanham
G
G
D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D018664:Interleukin-12 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000097:blood; D015851:Interleukin-7 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D018121:Receptors, Cytokine / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020395:Receptors, Interleukin-7; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D007376:Interleukin-2; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma