Pertussis toxin-driven IL-1β production is required for priming of highly encephalitogenic GM-CSF+ T cells and for EAE pathogenesis
Research area: Cellular Immunology
Group leaders: Federica Sallusto
Status: In progress
IL-1β is a pleiotropic cytokine that plays a role in several inflammatory disorders in humans and in animal models, including mouse experimental autoimmune encephalomyelitis (EAE). It is produced after cleavage of pro-IL-1β by IL-1 converting enzyme (caspase-1), which in turn is activated by a complex of proteins called inflammasome. IL-1β has been shown to be required for differentiation of human and mouse inflammatory Th17 cells characterized by co-expression of IL-17 and IFN-γ. We found that mice deficient for IL-1β or for a component of the inflammasome (the apoptosis-associated speck-like protein containing a caspase recruitment domain, ASC) did not develop EAE following immunization with myelin oligodendrocyte glycoprotein (MOG) in complete Freund’s adjuvant (CFA) and pertussis toxin (PT). Autoreactive T cells were primed in wild-type (wt), IL-1β–/– and ASC–/– mice. However, while in wt mice T cells proliferated extensively and acquired the capacity to produce inflammatory cytokines, such as IL-17, IL-22, IFN-γ, and GM-CSF, in IL-1β–/– and ASC–/– mice, cells expanded poorly and showed reduced capacity to produce simultaneously inflammatory cytokines, in particular GM-CSF. Interestingly, induction of polyfunctional (IL-17+ IL-22+ IFNγ+ GM-CSF+) T cells in wt mice was dependent on the presence of PT at the time of immunization. PT was found to rapidly induce IL-1β secretion by CD11c+ and Gr1+ myeloid cells, which are highly recruited in secondary lymphoid organs after in vivo PT treatment. Moreover, in mice depleted of Gr1+ myeloid cells, IL-1β production was not induced by PT and priming of polyfunctional T cells was impaired. Taking together, these data support the notion that the disease-inducing effect of PT is due to its ability to induce recruitment of Gr1+ myeloid cells, production of IL-1β, and differentiation of pathogenic polyfunctional T cells.