DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells

Keisuke Matsubara, Kazufumi Kunimura, Nana Yamane, Ryosuke Aihara, Tetsuya Sakurai, Daiji Sakata, Takehito Uruno, Yoshinori Fukui

Research output: Contribution to journalArticlepeer-review

Abstract

Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor (GEF) for Cdc42. In humans, homozygous or compound heterozygous deletions in DOCK8 cause a combined immunodeficiency characterized by various allergic diseases including food allergies. Although group 2 innate lymphoid cells (ILC2s) contribute to the development of allergic inflammation by producing interleukin (IL)-5 and IL-13, the role of ILC2s in DOCK8 deficiency has not been fully explored. With the use of cytometry by time-of-flight (CyTOF), we performed high-dimensional phenotyping of intestinal immune cells and found that DOCK8-deficient (Dock8−/−) mice exhibited expansion of ILC2s and other leukocytes associated with type 2 immunity in the small intestine. Moreover, IL-5– and IL-13–producing cells markedly increased in Dock8−/− mice, and the majority of them were lineage-negative cells, most likely ILC2s. Intestinal ILC2s expanded when DOCK8 expression was selectively deleted in hematopoietic cells. Importantly, intestinal ILC2 expansion was also observed in Dock8VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Our findings indicate that DOCK8 is a negative regulator of intestinal ILC2s to inhibit their expansion via Cdc42 activation, and that deletion of DOCK8 causes a skewing to type 2 immunity in the gut.

Original languageEnglish
Pages (from-to)135-140
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume559
DOIs
Publication statusPublished - Jun 25 2021

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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