WDFY4 is required for cross-presentation in response to viral and tumor antigens

Abstract

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8⁺ T cells by <i>Batf3-</i>dependent CD8α⁺/XCR1⁺ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain-containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to <i>Batf3</i> ^-/- mice, <i>Wdfy4</i> ^-/- mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against <i>Toxoplasma gondii</i> infection. However, similar to <i>Batf3</i> ^-/- mice, <i>Wdfy4</i> ^-/- mice failed to prime virus-specific CD8⁺ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.