T-HELPER TYPE 1 T HELPER TYPE-2 CYTOKINES AND T-CELL DEATH - PREVENTIVE EFFECT OF INTERLEUKIN-12 ON ACTIVATION-INDUCED AND CD95 (FAS/APO-1)-MEDIATED APOPTOSIS OF CD4(+) T-CELLS FROM HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PERSONS/

Human immunodeficiency virus (HIV) infection leads to a progressive lo ss of CD4(+) T helper (Th) type 1 cell-mediated immunity that is assoc iated with defective in vitro CD4(+) T cell proliferation and abnormal T cell death by apoptosis in response to T cell receptor (TCR) stimul ation. Quantification of interleukin (IL)-2, interferon gamma, IL-4, I L-5, and IL-10 secretion by immunoassays, and of interferon gamma, IL- 4 and IL-10 messenger RNA expression by competitive reverse transcript ase polymerase chain reaction after in vitro stimulation of the TCR re vealed a similar Th1 cytokine profile in T cells from HIV-infected per sons and from controls. These data indicated that the loss of CD4(+) T h1 cell function in HIV-infected persons is not related to a Th1 to Th 2 cytokine switch as previously proposed, but to a process of activati on-induced death of CD4+ Th1 cells. Despite the absence of elevated le vels of Th2 cytokines, apoptosis of CD4(+) T cells, but not of CD8(+) T cells, was prevented in vitro by antibodies to IL-10 or IL-4, two Th 2 cytokines that downregulate Th1 cell responses, or by the addition o f recombinant IL-12, a cytokine that upregulates Th1 functions. TCR-in duced apoptosis of cell hybridomas and preactivated T cells has been s hown to involve the CD95 (Fas/Apo-1) molecule. CD4(+) and CD8(+) T cel ls from HIV-infected persons expressed high levels of the CD95 molecul e, and, in contrast to T cells from controls, were highly sensitive to antibody-mediated CD95 ligation, which induced apoptosis in a percent age of T cells similar to that induced by TCR stimulation. As TCR-indu ced apoptosis, CD95-mediated apoptosis of CD4+ T cells, but not of CD8 (+) T cells, was prevented by the addition of recombinant IL-12. Toget her, these findings suggest that apoptosis of CD4(+) T cells from HIV- infected persons involves an abnormal sensitivity to CD95 ligation, an d to TCR stimulation in the presence of normal levels of Th2 cytokines . The preventive effect of IL-12 on both mechanisms has potential impl ications for the design of immunotherapy strategies aimed at the upreg ulation of CD4(+) Th1 cell functions in AIDS.