Antigen-Antibody Immune Complexes Empower Dendritic Cells to Efficiently Prime Specific CD8+ CTL Responses In Vivo

Abstract

Dendritic cells (DCs) require a maturation signal to acquire efficient CTL-priming capacity. In vitro FcgammaR-mediated internalization of Ag-Ab immune complexes (ICs) can induce maturation of DCs. In this study, we show that IC-induced DC maturation in vitro enables DCs to prime peptide-specific CD8+ CTLs in vivo, independently of CD4+ Th cells. Importantly, OVA/anti-OVA IC-treated DCs not only primed CD8+ CTLs to an exogenously loaded peptide nonrelated to OVA, but also efficiently primed CTLs against the dominant CTL epitope derived from the OVA Ag present in the ICs. Our studies show that ICs fulfill a dual role in priming of CD8+ CTL responses to exogenous Ags: enhancement of Ag uptake by DCs and activation of DCs, resulting in "license to kill." These findings indicate that the presence of specific Abs can crucially affect the induction of cytotoxic cellular responses.

A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation

“…The production of IL-12 by activated DCs has been linked to polarization of the Th responses toward Th1. Fc␥R engagement induces IL-12 production, and has also been shown to effectively prime CTL responses in vivo (30), suggesting that DC activation by ICs would result in Th1 polarization. In contrast, macrophages were recently reported to reverse a Th1-like response toward a Th2-like phenotype when Ag was targeted on Fc␥R (31).…”

Requirements of NK Cells and Proinflammatory Cytokines in T Cell-Dependent Neonatal Autoimmune Ovarian Disease Triggered by Immune Complex

“…However, in vitro studies have shown that Ab, by forming immune complex with the Ag, can also significantly affect the T cell response. Engagement of immune complex with FcRs on APCs results in a Ͼ1000-fold increase in Ag uptake (1), induces maturation and cytokine production by dendritic cells (DC) 3 (2,3), and promotes the T cell response. Ab also affects Ag processing by APC and selection of the cognate T cell peptides for presentation (4).…”

Mini‐review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross‐priming and direct priming?

“…If receptor-mediated antigen-ingestion does not simultaneously activate the DC, as is the case e.g. in our study of ingestion of immune complexes [23], cross-tolerance may ensue. Targeting of antigen to DEC 205 indeed led to CD4 + T cell tolerance [33] or CD8 + T cell tolerance [34].…”

“…Recently it was shown that another highly efficient pathway of cross-priming of CD8 + CTL involves Fc + Rmediated ingestion of protein-IgG-antibody complexes by DC [22,23]. The Fc + R capture of immune complexes not only led to an impressive increase in efficiency of protein-antigen uptake, but Fc + R triggering by the complexes also caused the DC activation required for CD8 + CTL response induction [22,23].…”

“…The Fc + R capture of immune complexes not only led to an impressive increase in efficiency of protein-antigen uptake, but Fc + R triggering by the complexes also caused the DC activation required for CD8 + CTL response induction [22,23]. In an independent study, this mechanism was used for effective CTLmediated tumor immunity in vivo [24].…”