Editors' ChoiceImmunology

FcγRs Muscle Up Dendritic Cell Cross-Presentation

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Science Translational Medicine  09 Jan 2013:
Vol. 5, Issue 167, pp. 167ec5
DOI: 10.1126/scitranslmed.3005595

Methods of training the immune system to outsmart cancer cells and viral infections center on rational design: harnessing and targeting specialized immune cells to best solicit and optimize function. One commonly sought strategy is to deliver viral and tumor proteins to dendritic cells, potent antigen-presenting cells specialized to prime T cells with great efficiency. In humans, the subset of dendritic cells in the blood and tissue that expresses the cell-surface marker BDCA3 is specialized at presenting proteins to T cells from dying necrotic cells, such as those infected by virus, through a process known as cross-presentation. These cells thus are an ideal vehicle of external antigen delivery to stimulate T cells, and several clinical trials and immunization strategies aim to improve uptake of cancer and viral proteins by BDCA3+ dendritic cells.

Now, Flinsenberg and colleagues have targeted antigen delivery to BDCA3+ dendritic cells by capitalizing on the endogenous pathway by which blood-borne antigens cleared by antibodies and coated with complement proteins get taken up by dendritic cells. They examined the role of antibody receptors—Fcγ receptors (FcγRs)—in mediating cross-presentation by different human dendritic cell subsets. To do this, the authors focused on cytomegalovirus (CMV) infection, a major viral threat for immunosuppressed individuals receiving organ transplants. They first demonstrated dendritic cells grown from monocytes in culture-expressed FcγRs on their cell surface and could stimulate CD8+ T cells in response to a CMV antigen. The CMV-specific T cell response was enhanced by addition of antibodies against the CMV antigen and inhibited by blocking antibodies against Fc receptors. Thus, Fc receptor uptake was needed for the enhanced cross-presentation.

The authors then addressed the basis for improved cross-presentation. They addressed whether antibody addition improved the capture of antigen or changed the maturation status of the dendritic cells. Neither process was substantially changed by antibody addition. However, addition of drugs that inhibit both the proteosome and endosomal transport blocked cross-presentation of FcγR-targeted viral antigen, suggesting that both processes were required by the dendritic cells. These findings in cultured cells also translated to BDCA3+ cross-presenting dendritic cells isolated from blood and tonsils, which express FcγRs that facilitated enhanced antigen cross-presentation.

Technical optimization of individual ratios of antigen-antibody complexes and the need to individually optimize culture settings creates some barrier to direct human translation and immediate clinical vaccine strategies. However, this study reveals an important strategy for enhanced cross-presentation through Fc receptor–based antigen targeting and importantly sheds light on new fundamental properties of cross-presentation, such as proteosomal dependence. Now, researchers can better understand and further improve anticancer and viral vaccine strategies that target antigens to cross-presentation by specialized human dendritic cells.

T. W. H. Flinsenberg et al., Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells. Blood. 120, 5163–5172 ( 2012). [Abstract]

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