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

Humans with inherited defects inDOCK8expression are prone to allergic, type 2 CD4(+)T cell responses. Mandl and colleagues reveal an important role for cell death in driving such type 2 signals during infection. 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 inDOCK8, 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 (T(H)2) cell bias upon pulmonary infection withCryptococcus neoformansand other non-T(H)2 stimuli. We found that recruitedDock8(-/-)CX3CR1(+)mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1 beta that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4(+)T cells. Blocking IL-1 beta, GM-CSF or caspase activation eliminated the type-2 skew in mice lackingDock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and T(H)2 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.