DIFFERENTIAL SUSCEPTIBILITY TO ACTIVATION-INDUCED APOPTOSIS AMONG PERIPHERAL TH1 SUBSETS - CORRELATION WITH BCL-2 EXPRESSION AND CONSEQUENCES FOR AIDS PATHOGENESIS

It has been proposed that HIV infection is associated with an imbalanc e in Th1 and Th2 subsets. Recent reports indicate that Th1 and Th2 eff ecters differ in their susceptibility to activation-induced apoptosis. To determine whether increased T cell apoptosis in HIV-infected patie nts contributes to alterations in cytokine synthesis, we performed sin gle-cell analysis of type 1 and type 2 cytokine production by CD4 and CD8 T cells, simultaneously with detection of apoptosis. We demonstrat e that a differential alteration in representation of Th1 subsets, rat her than commitment of T cells to secrete Th2 cytokines, occurs throug hout HIV infection. A significant decrease in the number of IL-2- or T NF-alpha-producing T cells was observed, whereas those producing IFN-g amma remained preserved. Furthermore, there is a gradient of susceptib ility to activation-induced apoptosis (IL-2 < IFN-gamma < TNF-alpha) a mong the different Th1 subsets. This gradient was detected in both CD4 and CD8 subsets, as well as in control donors and HIV-infected patien ts, in whom the susceptibility to apoptosis of IL-2 and IFN-gamma prod ucers was increased compared with controls. This differential intrinsi c apoptosis susceptibility of Th1 effectors was found to be tightly re gulated by Bcl-2 expression. In HIV-infected persons, disappearance of IL-2-producing T cells was a good indicator of disease progression an d was correlated with the progressive shrinkage of the CD4(+)CD45RA(+) T cell compartment and a gradual increased susceptibility to activati on-induced apoptosis of the IL-2-producing subset. This close relation ship between the CD45RA/CD35R0 ratio, the level of type 1 cytokine pro duction, and susceptibility to apoptosis should be considered in HIV-i nfected patients under antiviral or immune-based therapies.