Skewed expression and up-regulation of the IL-12 and IL-18 receptors in resting and activated CD4 T cells from HIV-1-infected patients.
IL-12 and IL-18 synergistically induce the production of IFN-gamma by resting and activated T cells. To evaluate whether this induction was affected in HIV-1-infected patients, PBMC or isolated CD4 T cells were cultured with IL-12 plus IL-18, anti-CD3 plus anti-CD28, or PHA for 72 h. Cell samples were labeled daily to assess the levels of IL-12 receptor beta1 (IL-12Rbeta1), IL-12Rbeta2, and IL-18Ralpha. Culture supernatants were analyzed for the presence of Th1- and Th2-related cytokines by ELISA or cytometric bead array and analyzed by flow cytometry. A twofold increase in the percentage of CD4-resting T cells expressing IL-12Rbeta1 and IL-18Ralpha from HIV-1-infected patients was observed when compared with cells from HIV-1-negative donors. Higher IL-12Rbeta1 and IL-18Ralpha expression correlated (r=0.87; P<0.007) to increased production of IFN-gamma by isolated CD4 T cells in the presence of IL-12 and IL-18. Moreover, exogenous IL-12 and IL-18 induced the up-regulation of IL-12Rbeta2 to twice higher in CD4 T cells from HIV-1-positive individuals compared with controls. Conversely, upon activation with anti-CD3 and anti-CD28 antibodies, only 25% of the CD4+ T cells from HIV-1 patients showed an increase in the IL-12beta2 when compared with 50% in healthy controls. Furthermore, the percentage of IL-12Rbeta1-positive cells correlated inversely with the CD4 nadir of patients, suggesting that deregulation of the IL-12 and IL-18 pathways may play a role in the immunopathogenesis of HIV-1 infection.
de Arquer
Guillermo Robert
GR
Fundació IrsiCaixa, HIVACAT, Hospital Universitari Germans Trias i Pujol, Ctra Canyet sn, 08916 Badalona, Spain.
Peña
Ruth
R
Cabrera
Cecilia
C
Coma
Gemma
G
Ruiz-Hernandez
Raul
R
Guerola
Rosa
R
Clotet
Bonaventuta
B
Ruiz
Lidia
L
Esté
José A
JA
Calle
M Luz
ML
Bofill
Margarita
M
D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000209:etiology / Q000235:genetics*; D015497:HIV-1; D006801:Humans; D008213:Lymphocyte Activation; D053707:Receptors, Interleukin-12 / Q000235:genetics*; D053724:Receptors, Interleukin-18 / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18