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

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8⁺ T cells by Batf3-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 Batf3 ^-/- mice, Wdfy4 ^-/- mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3 ^-/- mice, Wdfy4 ^-/- 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. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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