Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15.

Abstract

SummaryCytokines have been shown to be powerful regulators of the immune response. In this study, we analyze the effect that the newly recognized cytokine interleukin (IL)-15 has on proliferation and cytokine induction 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 enhances the proliferative response in a dose-dependent manner from PBMCs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toxoid, or HIV-specific antigen. The effects of exogenous IL-15 are substantially diminished by adding a neutralizing antibody to the [3 chain of the IL-2 receptor. Moreover, the ability of IL-15 to increase proliferation is enhanced by the presence of endogenous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2, IL-4, and interferon (IFN)-y induction from PBMC's or CD4 + T cells in response to mitogen or tetanus toxoid 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 cultures of either PBMCs or CD4 + T cells had little effect on IL-2, IL-4, or IFN-~/production. By contrast, IL-12 caused substantial enhancement of both IL-2 and IFN-',/ production from these cultures. The role that endogenous cytokines have on IFN-y induction was also studied. Addition of a neutralizing antibody to the cx chain of the IL-2 receptor or IL-12 to antigen stimulated cultures caused a striking decrease in IFN-y production. Neutralization of endogenous IL-15 also resulted in diminished IFN-y production from cultures stimulated with mitogen. IL-4 and IFN-~/protein production by PBMCs and CD4 + T cells stimulated with mitogen was assessed to see if we could detect a specific bias of cytokine production. Small amounts oflL-4 were detected from CD4 + T cells but not PBMCs from most individuals tested. IFN-y and IL-2, however, were also produced from these same cultures. These results further elucidate the mechanism ofcytokine regulation in HIV-infected individuals, and they provide evidence that IL-15 may be a useful immune modulator.

IL-2 Receptor Blockade Inhibits Late, But Not Early, IFN-γ and CD40 Ligand Expression in Human T Cells: Disruption of Both IL-12-Dependent and -Independent Pathways of IFN-γ Production

“…Since clinical trials have shown HAT to be an effective therapy in both these settings, we focused on the mechanism(s) by which HAT inhibits IFN-␥ production. Earlier studies had noted that anti-Tac inhibits IFN-␥ production from T cell clones or PHA-stimulated PBMC but did not explore the basis of this inhibition (21,22). In our studies, intracellular cytokine staining at the peak of IFN-␥ production (48 h) revealed that HAT inhibits IFN-␥ expression in both CD4 and CD8 T cells, independent of CD28 costimulation.…”

IL‐15‐induced human DC efficiently prime melanoma‐specific naive CD8+ T cells to differentiate into CTL

“…IL-15 itself induces in vitro antigen-independent expansion of human naive CD8 + T cells [18] and enhances antigen-specific proliferation of T cells isolated from HIV-infected patients [19]. Yet, the mere action of soluble IL-15 cannot explain the enhanced priming by IL15-DC, as the preferential expansion of CD8 + T cells depends upon cell-cell contact.…”

Differential Role for IL‐2 and IL‐15 in the Inhibition of Apoptosis in Short Term Activated Human Lymphocytes

“…Both cytokines are therefore mutually exclusive in their production in various cell types [34]. Even though their amino acid sequence shows no homology [34,36], the biological action of both proteins seems to be similar as activators of CD4 + and CD8 + T lymphocytes, gd T cells, NK cells and B lymphocytes [40][41][42][43][44][45][46]. This could be explained by the observation that both IL-2 and IL-15 bind to the IL-2R b-and g cchain [34,36].…”