| First Author | Schneider C | Year | 2020 |
| Journal | Nat Immunol | Volume | 21 |
| Issue | 12 | Pages | 1528-1539 |
| PubMed ID | 33020661 | Mgi Jnum | J:306560 |
| Mgi Id | MGI:6706679 | Doi | 10.1038/s41590-020-0795-1 |
| Citation | Schneider C, et al. (2020) Migration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response. Nat Immunol 21(12):1528-1539 |
| abstractText | 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)-1beta that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4(+) T cells. Blocking IL-1beta, 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. |
