Using cDC1 from murine bone marrow and whole cells as antigens, Theisen et al. conducted a CRISPR screen to identify genes involved in cross-presentation and uncovered WDFY4. cDC1s from WDFY4-/- mice were unable to cross-present whole cell antigens but were fully capable of presenting soluble antigens, cytoplasmic antigens, or MHC class II epitopes and demonstrated all other relevant DC functions (phagocytosis, upregulation of co-stimulatory molecules, production of IL-12). The membrane protein WDFY4 appears to be important in proper intracellular trafficking of endocytosed whole cell antigens, such as virally infected or tumor cells.
During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8(+) T cells by Batf3-dependent CD8alpha(+)/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.
Author Info: (1) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (2) Department of Pathology and Immunology, Washington University Sc
Author Info: (1) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (2) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. (3) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (4) Department of Experimental Medicine, University of Perugia, Perugia, Italy. (5) Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (6) Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. (7) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. (8) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (9) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (10) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (11) Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. (12) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Vir Biotechnology, San Francisco, CA, USA. (13) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110, USA. (14) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (15) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. (16) Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. (17) Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (18) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. (19) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (20) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. kmurphy@wustl.edu. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
