Differential susceptibility to activation-induced apoptosis among peripheral Th1 subsets: correlation with Bcl-2...

It has been proposed that HIV infection is associated with an imbalance in Th1 and Th2 subsets. Recent reports indicate that Th1 and Th2 effectors differ in their susceptibility to activation-induced apoptosis. To determine whether increased T cell apoptosis in HIV-infected patients contributes to alterations in cytokine synthesis, we performed single-cell analysis of type 1 and type 2 cytokine production by CD4 and CD8 T cells, simultaneously with detection of apoptosis. We demonstrate that a differential alteration in representation of Th1 subsets, rather than commitment of T cells to secrete Th2 cytokines, occurs throughout HIV infection. A significant decrease in the number of IL-2- or TNF-alpha-producing T cells was observed, whereas those producing IFN-gamma remained preserved. Furthermore, there is a gradient of susceptibility to activation-induced apoptosis (IL-2 < IFN-gamma < TNF-alpha) among the different Th1 subsets. This gradient was detected in both CD4 and CD8 subsets, as well as in control donors and HIV-infected patients, in whom the susceptibility to apoptosis of IL-2 and IFN-gamma producers was increased compared with controls. This differential intrinsic apoptosis susceptibility of Th1 effectors was found to be tightly regulated by Bcl-2 expression. In HIV-infected persons, disappearance of IL-2-producing T cells was a good indicator of disease progression and was correlated with the progressive shrinkage of the CD4+ CD45RA+ T cell compartment and a gradual increased susceptibility to activation-induced apoptosis of the IL-2-producing subset. This close relationship between the CD45RA/CD45R0 ratio, the level of type 1 cytokine production, and susceptibility to apoptosis should be considered in HIV-infected patients under antiviral or immune-based therapies.