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

Science. 2018 Nov 9;362(6415):694-699. doi: 10.1126/science.aat5030.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Antigens, Viral / immunology*
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / physiology
  • CD8-Positive T-Lymphocytes / immunology
  • CRISPR-Cas Systems
  • Cross-Priming / genetics*
  • Genetic Testing
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology
  • Toxoplasma / immunology
  • Toxoplasmosis / immunology

Substances

  • Antigens, Neoplasm
  • Antigens, Viral
  • Basic-Leucine Zipper Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Repressor Proteins
  • SNFT protein, mouse
  • Wdfy4 protein, mouse