Enhancing Antigen Cross-Presentation in Human Monocyte-Derived Dendritic Cells by Recruiting the Intracellular Fc Receptor TRIM21.

ABSTRACT

Suboptimal immune responses to pathogens contribute to chronic infections. One way to improve immune responses is to boost Ag presentation. In this study, we investigate the potential of the tripartite motif-containing 21 (TRIM21) pathway. TRIM21 is a ubiquitously expressed cytosolic protein that recognizes the Fc region of Abs. When Abs that are bound to pathogens enter the cell as immune complexes, binding of TRIM21 to Fc initiates downstream inflammatory signaling and targets the immune complexes for proteasomal degradation. In APCs, peptides generated by proteasomes are loaded onto MHC class I molecules to stimulate CD8 T cell responses, which are crucial for effective immunity to pathogens. We hypothesized that increasing the affinity between immune complexes and TRIM21 might markedly improve CD8 T cell responses to Ags processed by the TRIM21 pathway. Using phage display technology, we engineered the human IgG1 Fc to increase its affinity for TRIM21 by 100-fold. Adenovirus immune complexes with the engineered Fc induced greater maturation of human dendritic cells (DC) than immune complexes with unmodified Fc and stimulated increased Ag-specific CD8 T cell proliferation and IFN-γ release in cocultures of DC-PBMC. Thus, by increasing the affinity between Fc and TRIM21, Ags from immune complexes undergo enhanced cross-presentation on DC, leading to greater CD8 T cell responses. Our study reveals an approach that could potentially be used in vaccines to increase cytotoxic T cell responses against Ags that are targeted or delivered by Fc-modified Abs.