Migration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response

Nat Immunol. 2020 Dec;21(12):1528-1539. doi: 10.1038/s41590-020-0795-1. Epub 2020 Oct 5.


Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8-/- mice have a profound type 2 CD4+ helper T (TH2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-TH2 stimuli. We found that recruited Dock8-/-CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1β that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4+ T cells. Blocking IL-1β, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and TH2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4+ T cell responses in allergic disease.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers
  • Caspases / metabolism
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Susceptibility
  • Gene Expression
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Guanine Nucleotide Exchange Factors / deficiency*
  • Humans
  • Immunophenotyping
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Activation / genetics*
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Knockout
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Phagocytes / immunology
  • Phagocytes / metabolism
  • Signal Transduction
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism*


  • Biomarkers
  • Cytokines
  • DOCK8 protein, human
  • Guanine Nucleotide Exchange Factors
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Caspases