Kinetics of γ interferon binding and induction of major histocompatibility complex class II mRNA in Leishmania-infected macrophages

Abstract

Cells of the monocyte-macrophage series must carry out discrete accessory-cell functions during the process of antigen-specific T-cell activation. One of these functions is the cell-surface expression of major histocompatibility complex (MHC) class II gene products, which are involved in the presentation of foreign antigen to T cells. Previously, we reported that murine peritoneal macrophages infected with the obligate intracellular protozoan Leishmania donovani had suppressed responses to γ interferon (IFN-γ) for the induction of MHC class II antigen expression. To determine the molecular basis for this suppression we examined in the present series of experiments the interaction of this organism with cells of the murine macrophage tumor cell line P388D1. When infected with Leishmania, these cells were also markedly unresponsive to IFN-γ for the induction of MHC class II antigen expression. This finding was not the result of a defect at the level of the IFN-γ receptor. Thus, when 125I-labeled IFN-γ was used, infected macrophages were found to express normal numbers of high-affinity IFN-γ receptors, and ligand-receptor binding resulted in rapid internalization of labeled IFN-γ. Despite normal ligand-receptor interactions, the induction in infected cells of mRNA encoding MHC (H-2) class II I-A α and β chains in response to IFN-γ was markedly suppressed. However, infected cells had normal levels of mRNA encoding the cytoskeletal protein actin. These findings indicate that Leishmania interferes with IFN-γ induction of macrophage MHC class II antigen expression by down-regulating lymphokine induction of MHC class II mRNA. Suppression of class II expression by this intracellular parasite may prevent subsequent T-cell recognition of infected macrophages and thus favor parasite survival.