Human Dendritic Cells Discriminate Between Viable and KilledToxoplasma gondiiTachyzoites: Dendritic Cell Activation After Infection with Viable Parasites Results in CD28 and CD40 Ligand Signaling That Controls IL-12-Dependent and -Independent T Cell Production of IFN-γ

Abstract

We studied how the interaction between human dendritic cells (DC) and Toxoplasma gondii influences the generation of cell-mediated immunity against the parasite. We demonstrate that viable, but not killed, tachyzoites of T. gondii altered the phenotype of immature DC. DC infected with viable parasites up-regulated the expression of CD40, CD80, CD86, and HLA-DR and down-regulated expression of CD115. These changes are indicative of DC activation induced by T. gondii. Viable and killed tachyzoites had contrasting effects on cytokine production. DC infected with viable T. gondii rather than DC that phagocytosed killed parasites induced secretion of high amounts of IFN-γ by T cells from T. gondii-seronegative donors. IFN-γ production in response to DC infected with viable parasites required CD28 and CD40 ligand (CD40L) signaling. In addition, this IFN-γ response was dependent in part on IL-12 secretion. Production of IL-12 p70 occurred after interaction between T cells and DC infected with viable T. gondii, but not after incubation of T cells with DC plus killed tachyzoites. IL-12 synthesis was inhibited by blockade of CD40L signaling. IL-12-independent IFN-γ production required CD80/CD86-CD28 interaction and, to a lesser extent, CD40-CD40L signaling. Taken together, T. gondii-induced activation of human DC is associated with T cell production of IFN-γ through CD40-CD40L-dependent release of IL-12 and through CD80/CD86-CD28 and CD40-CD40L signaling that mediate IFN-γ secretion even in the absence of bioactive IL-12.

Avirulent Uracil Auxotrophs Based on Disruption of Orotidine-5′-Monophosphate Decarboxylase Elicit Protective Immunity to Toxoplasma gondii

“…In contrast, immunization with T. gondii extracts or killed noninvasive intact parasites does not elicit significant immunity to reinfection with T. gondii (2,40). Only actively infected host cells have been shown to prime CD8 ϩ T-cell-dependent immunity in T. gondii infection (10,20,21).…”

Role of CD40-Dependent Down-Regulation of CD154 in Impaired Induction of CD154 in CD4+ T Cells from HIV-1-Infected Patients

“…Monocyte-derived dendritic cells were obtained from healthy controls as previously described (22). Autologous CD4 ϩ T cells were incubated with adherent monocytes with or without SEB and anti-CD40 mAb as described above.…”

Parasite Manipulation of the Invariant Chain and the Peptide Editor H2-DM Affects Major Histocompatibility Complex Class II Antigen Presentation during Toxoplasma gondii Infection

“…Levels of MHC-II proteins are reduced in infected cells, antigen presentation is impaired, and priming and activation of CD4 ϩ T cells are greatly diminished (23,24,35), yet small amounts of MHC-II proteins are detected in these cells. Others have reported opposing views, where Toxoplasma activates human blood DCs upon invasion (36) and soluble T. gondii antigens (STAg) activate murine splenic CD8␣…”