TY - JOUR
T1 - DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells
AU - Matsubara, Keisuke
AU - Kunimura, Kazufumi
AU - Yamane, Nana
AU - Aihara, Ryosuke
AU - Sakurai, Tetsuya
AU - Sakata, Daiji
AU - Uruno, Takehito
AU - Fukui, Yoshinori
N1 - Funding Information:
We thank Ayumi Inayoshi, Arisa Aosaka, Nao Kanematsu, Sayaka Akiyoshi and Satomi Hori for technical assistance. This work was supported by Leading Advanced Projects for Medical Innovation (LEAP, JP19gm0010001 ) and Advanced Research and Development Programs for Medical Innovation (AMED-CREST, JP20gm1310005 ) from Japan Agency for Medical Research and Development (to Y.F.).
Publisher Copyright:
© 2021 The Authors
PY - 2021/6/25
Y1 - 2021/6/25
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bbrc.2021.04.094
DO - 10.1016/j.bbrc.2021.04.094
M3 - Article
C2 - 33940384
AN - SCOPUS:85104920696
VL - 559
SP - 135
EP - 140
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
ER -