Immune Sensing of Cell Death through Recognition of Histone Sequences by C-Type Lectin-Receptor-2d Causes Inflammation and Tissue Injury

Immunity. 2020 Jan 14;52(1):123-135.e6. doi: 10.1016/j.immuni.2019.11.013. Epub 2019 Dec 16.


The immune system monitors the health of cells and is stimulated by necrosis. Here we examined the receptors and ligands driving this response. In a targeted screen of C-type lectin receptors, a Clec2d reporter responded to lysates from necrotic cells. Biochemical purification identified histones, both free and bound to nucleosomes or neutrophil extracellular traps, as Clec2d ligands. Clec2d recognized poly-basic sequences in histone tails and this recognition was sensitive to post-translational modifications of these sequences. As compared with WT mice, Clec2d-/- mice exhibited reduced proinflammatory responses to injected histones, and less tissue damage and improved survival in a hepatotoxic injury model. In macrophages, Clec2d localized to the plasma membrane and endosomes. Histone binding to Clec2d did not stimulate kinase activation or cytokine production. Rather, histone-bound DNA stimulated endosomal Tlr9-dependent responses in a Clec2d-dependent manner. Thus, Clec2d binds to histones released upon necrotic cell death, with functional consequences to inflammation and tissue damage.

Keywords: C-type lectin; Clec2d; DAMPs; Toll-like receptor; histone acetylation; histones; inflammation; liver injury; macrophages; pattern recognition receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Endosomes / metabolism
  • HEK293 Cells
  • Histones / metabolism*
  • Humans
  • Jurkat Cells
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology*
  • Lectins, C-Type / metabolism*
  • Liver / injuries*
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis / pathology*
  • Neutrophils / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Receptors, Cell Surface / metabolism*
  • Toll-Like Receptor 9 / immunology


  • CLEC2D protein, human
  • Histones
  • Lectins, C-Type
  • Receptors, Cell Surface
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9