CYTOKINE INTERACTIONS IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED INDIVIDUALS - ROLES OF INTERLEUKIN (IL)-2, IL-12, AND IL-15

Cytokines have been shown to be powerful regulators of the immune resp onse. In this study, we analyze the effect that the newly recognized c ytokine interleukin (IL)-15 has on proliferation and cytokine inductio n using peripheral blood mononuclear cells (PBMCs) and purified CD4(+) T cells from patients infected with human immunodeficiency virus (HIV ) who are at various stages in their disease. We observed that IL-15 e nhances the proliferative response in a dose-dependent manner from PBM Cs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toroid, or HIV-specific antigen. The effects of exogenous IL-1 5 are substantially diminished by adding a neutralizing antibody to th e beta chain of the IL-2 receptor. Moreover, the ability of IL-15 to i ncrease proliferation is enhanced by the presence of endoge- nous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2 , IL-4, and interferon (IFN)-gamma induction from PBMC's or CD4(+) T c ells in response to mitogen or tetanus toroid was also examined. This was compared to the effect that exogenous IL-2 and IL-12 had under the same conditions. Addition of IL-2 or IL-15 to short-term in vitro cul tures of either PBMCs or CD4(+) T cells had little effect on IL-2, IL- 4, or IFN-gamma production. By contrast, IL-12 caused substantial enha ncement of both IL-2 and IFN-gamma production from these cultures. The role that endogenous cytokines have on IFN-gamma induction was also s tudied. Addition of a neutralizing antibody to the cr chain of the IL- 2 receptor or IL-12 to antigen stimulated cultures caused a striking d ecrease in IFN-gamma production. Neutralization of endogenous IL-15 al so resulted in diminished IFN-gamma production from cultures stimulate d with mitogen. IL-4 and IFN-gamma protein production by PBMCs and CD4 (+) T cells stimulated with mitogen was assessed to see if we could de tect a specific bias of cytokine production. Small amounts of IL-4 wer e detected from CD4(+) T cells but not PBMCs from most individuals tes ted. IFN-gamma and IL-2, however, were also produced from these same c ultures. These results further elucidate the mechanism of cytokine reg ulation in HIV- infected individuals, and they provide evidence that I L-15 may be a useful immune modulator.