Fcγ Receptors and Cross-Presentation in Dendritic Cells

M. Bevan showed in the mid-seventies that cytotoxic T lymphocyte (CTL) responses may be initiated by antigen-presenting cells that do not express the antigens themselves (1). He called this process cross-priming. The antigen-presenting cells involved in cross-priming must therefore inter-nalize and present antigens to CD8 ϩ T cells in the context of MHC class I molecules. This process is often referred to as " cross-presentation. " Cross-presentation by antigen-presenting cells in vivo results in either cross-priming (initiation of CD8 ϩ T cell responses) or in cross-tolerance (induction of CD8 ϩ T cell unresponsiveness; reference 2). These results raised the question of the nature of the " cross-presenting cells. " In vitro, dendritic cells cross-present anti-gens more efficiently than any other antigen-presenting cell (3). They are also the only antigen-presenting cells that activate naive T lymphocytes (4). Dendritic cells, indeed, are sufficient for cross-presentation in vivo (5). Fc Receptors (FcRs) and Cross-Presentation in Dendritic Cells. If cross-presentation is how dendritic cells initiate CTL responses, antigen targeting to and internalization by dendritic cells must represent a critical step in cross-priming. In vitro, targeting antigens to receptors for the Fc region (Fc ␥ R) of IgG, dramatically increases the efficiency of cross-presentation (3). Fc ␥ Rs are a family of membrane glycoproteins expressed on hematopoietic cells (6). Most Fc ␥ Rs do not bind IgG, unless IgGs are themselves bound to multivalent-specific antigens (i.e., immune complexes). Thus, Fc ␥ RII (CD32) and Fc ␥ RIII (CD16) bind monomeric IgG quite inefficiently , but bind immune complexes with very high affinity. Fc ␥ RI (CD64), in contrast, binds monomeric IgG with high affinity, but, like high affinity receptors for IgE, it does not signal unless IgGs are cross-linked by their specific polymeric ligands. Thus, Fc ␥ Rs may be functionally considered as antigen receptors. Targeting antigens to Fc ␥ R promotes cross-presentation by several orders of magnitude in mouse bone marrow– derived dendritic cells (7, 8). The intracellular mechanisms leading to cross-presentation after Fc ␥ R-mediated uptake have been analyzed. In dendritic cells, but not in other cell types, Fc ␥ R-mediated internalization very efficiently targets antigen for a unique dendritic cell–specific antigen transport pathway resulting in delivery to the cytosol. Once in the cytosol, internalized antigens are degraded by the proteasome. The resulting peptides are translocated into the lumen of the ER and loaded on MHC class I molecules (9). These results suggested …