WDFY4 is required for classic dendritic cell–mediated cross-presentation of tumor and viral antigens.
Major finding: WDFY4 is required for classic dendritic cell–mediated cross-presentation of tumor and viral antigens.
Mechanism: WDFY4 interacts with endosomal membranes to promote endosomal-to-cytosol antigen trafficking.
Impact: Therapeutic activation of WDFY4-mediated cross-presentation may enhance immunotherapy efficacy.
The ability of lymphocytes to recognize microbial and tumor-associated antigens is mainly dependent upon the binding affinity of surface MHC-I for peptides. The MHC-I antigen–presenting classical dendritic cells (cDC) are comprised of BATF3-dependent cDC1s, which mediate cross-presentation of tumor and viral MHC-I antigens, and cDC2s, which mediate cross-presentation of pathogen MHC-I antigens. To further elucidate the mechanisms underlying cDC1–mediated cross-presentation, Thiesen, Davidson, and colleagues established a functional CRISPR/Cas9 screen to identify regulators of cross-presentation in cDC1s. The in vitro CRISPR/Cas9 screen demonstrated that loss of WDFY4, a transmembrane protein that is a member of the BEACH domain–containing protein family of scaffolding proteins, resulted in impaired mouse cDC1–mediated cross-presentation. While cDC1s developed normally in Wdfy4−/− but not Batf3−/− mice, the cDC1-mediated cytotoxic CD8+ T-cell response to the presence of cell-associated or bacterial antigens was ablated in vitro in Wdfy4−/− mice. Affinity purification mass spectrometry identified interactions between WDFY4 and proteins involved in assembling protein complexes and subcellular vesicular trafficking, particularly the formation and trafficking of endocytic vesicles. In particular, WDFY4 was selectively associated with HSP90AB1, which is involved in the processing of antigens during cross-presentation and shown to be co-localized with early endosomes and the ER near the plasma membrane. A highly immunogenic murine fibrosarcoma was rejected by control, Wdfy4+/− mice, and mice transplanted with mixtures of control and Batf3−/− bone marrow; conversely, the same murine fibrosarcoma grew in Batf3−/−, Wdfy4−/− mice, and mice transplanted with mixtures of Wdfy4−/− and Batf3−/− mice, suggesting that the failure to reject tumors was due to the loss of Wdfy4 in cDC1s. Similarly, tumors in Wdfy4−/− mice exhibited cDC1 infiltration and decreased CD8+ T-cell infiltration. These results identify WDFY4 as a critical regulator of cDC1-mediated cross-presentation of viral and tumor antigens and suggest potential avenues of preclinical investigation.
Theisen DJ, Davidson JT IV, Briseño CG, Gargaro M, Lauron EJ, Wang Q, et al. WDFY4 is required for cross-presentation in response to viral and tumor antigens. Science 2018;362:694–9.
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