Seminar - From beyond the grave: cell death and type-2 helper T cell differentiation

Immune cells are the only cells in the body able to migrate both between and within tissues. The importance of immune cell movement to immune system function is well illustrated in instances where mutations that impair migration cause immunodeficiency. In humans, loss-of-function mutations in DOCK8, which encodes for a guanine exchange factor involved in hematopoietic cell migration, lead to severe lymphopenia and, paradoxically, a high incidence of allergic disease, which is driven by type 2 CD4+ helper T (Th2) cells. We demonstrate that, like humans, Dock8-/- mice have a profound Th2 cell bias upon pulmonary infection with Cryptococcus neoformans or influenza A virus. We show that recruited Dock8-/- CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, activating caspase-1 and -3 and releasing interleukin (IL)-1β. Inhibiting IL-1β or caspase activation eliminates the type-2 skew in Dock8-deficient mice. Importantly, treating infected Dock8-/- mice that were given a pan-caspase inhibitor with exogenous IL-1b did not recapitulate the Th2 skew, indicating that IL-1b is necessary but not sufficient in the type-2 bias. Thus, we implicate an additional caspase-dependent co-signal in the Th2 skew. Remarkably, treatment of wild-type mice with dying cells during infection induced a type-2 biased CD4 T cell response, indicating that cell death favors Th2 differentiation even in a Dock8-sufficient context. Interestingly, we also find that unlike upon mucosal infections, systemic infection with lymphocytic choriomeningitis virus of Dock8-/- mice leads to a Th2 biased response in barrier tissues, but not in non-barrier organs, suggesting there are additional tissue-specific differences that permit the development of allergic pathology only in barrier surfaces. Together, our work reveals an important role for cell death and the tissue microenvironment in the etiology of Th2 responses, which may have implications for understanding the induction and rise of allergic diseases.