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TitleMigration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response.
Publication TypeJournal Article
Year of Publication2020
AuthorsSchneider, Caitlin, Connie Shen, Angelica A. Gopal, Todd Douglas, Benjamin Forestell, Keith D. Kauffman, Dakota Rogers, Patricio Artusa, Qian Zhang, Huie Jing, Alexandra F. Freeman, Daniel L. Barber, Irah L. King, Maya Saleh, Paul W. Wiseman, Helen C. Su, and Judith N. Mandl
JournalNat Immunol
Date Published2020 Oct 05
ISSN1529-2916
Abstract

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 (T2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-T2 stimuli. We found that recruited Dock8CX3CR1 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 T2 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.

DOI10.1038/s41590-020-0795-1
Alternate JournalNat Immunol
PubMed ID33020661
Grant List201603PJT-364017 / / Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre) /
MOP-130579 / / Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre) /