Immune complex–mediated antigen presentation induces tumor immunity

Abstract

Antigen uptake receptors on dendritic cells (DCs) provide efficient entry for the initiation of antigen-specific adaptive immunity. Here we show that targeting of antigen to Fc receptors on DCs accomplishes combined activation of Th1 CD4 and CD8 effector responses in vivo, namely delayedtype hypersensitivity and tumor immunity. Tumor immunity specific for ovalbumin-expressing tumors was provided by immunization with wild-type but not FcγRγ -/-DCs loaded with ovalbumincontaining immune complexes. Tumor protection was eliminated when immune complex-loaded DCs lacked β 2 microglobulin, TAP, or MHC class II, demonstrating that Fc receptor-targeted antigenic uptake led to both MHC class I-and class II-restricted responses, which together are required for effector tumor immunity. Thus the cross-presentation pathway accessed by antigens acquired endocytically through Fc receptors links humoral and cellular immunity. These data suggest that administration of antitumor antibodies may enhance tumor-specific T cell responses in vivo and provide the rationale for Fc receptor targeting in vaccine development.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Receptor-mediated endocytosis of immune complexes in rat liver sinusoidal endothelial cells is mediated by FcγRIIb2

“…This finding is in line with an observation (in bone marrow-derived dendritic cells) showing that in contrast to Fc␥RIII-mediated uptake of ICs, which leads to rapid delivery of the internalized IC to lysosomes, delivery of ICs to lysosomes is delayed after internalization by Fc␥RIIb, resulting in intracellular accumulation of undegraded ICs. 44 However, whether this also holds true for the in vivo situation is unclear, although studies in Kupffer cell-depleted rats, showing that the rate of degradation of aggregated IgG by LSECs is lower than that in normal animals, 45 suggest that endocytic processes similar to those observed in vitro also may occur in vivo.…”

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

“…ICs loaded on DCs could induce in vivo CD4 ϩ and CD8 ϩ CTL responses and mediate full tumor protection (30,37) correlated with induction of DC maturation. Syk-deficient DCs could not signal through the ␥-chain-dependent activating Fc␥Rs (type I and III), but Fc␥RIIB signaling (i.e., the recruitment of SHIP phosphatase; Ref.…”

“…A predominant inhibitory effect of Fc␥RIIB on tumor immunity and DC maturation has been suggested to induce tolerogenic DCs (36). However, another study showed that Fc␥R engagement in DCs Fc␥RI/II/III ϩ induces maturation and protective antitumor immune responses (37). These different studies have used DCs generated in vitro using slightly different protocols, which may account for the observed discrepancies.…”

Role of chaperones and FcγR in immunogenic death

“…The balance of activating versus inhibitory FcγRs may also be altered by cytokines, thereby regulating FcγR mediated cross presentation [44]. In mice genetically lacking inhibitory FcγRIIB, targeting immune complexes to DCs can lead to enhanced generation of antigen specific CD8+ T cell immunity in vitro and in vivo [45,46]. Likewise, genetic deletion of FcγRIIB leads to spontaneous autoimmunity in genetically prone mice [47].…”