IL-4Rα signaling by CD8α + dendritic cells contributes to cerebral malaria by enhancing inflammatory, Th1, and cytotoxic CD8 + T cell responses.

Persistent high levels of proinflammatory and Th1 responses contribute to cerebral malaria (CM). Suppression of inflammatory responses and promotion of Th2 responses prevent pathogenesis. IL-4 commonly promotes Th2 responses and inhibits inflammatory and Th1 responses. Therefore, IL-4 is widely considered as a beneficial cytokine via its Th2-promoting role that is predicted to provide protection against severe malaria by inhibiting inflammatory responses. However, IL-4 may also induce inflammatory responses, as the result of IL-4 action depends on the timing and levels of its production and the tissue environment in which it is produced. Recently, we showed that dendritic cells (DCs) produce IL-4 early during malaria infection in response to a parasite protein and that this IL-4 response may contribute to severe malaria. However, the mechanism by which IL-4 produced by DCs contributing to lethal malaria is unknown. Using Plasmodium berghei ANKA-infected C57BL/6 mice, a CM model, we show here that mice lacking IL-4Rα only in CD8α ⁺ DCs are protected against CM pathogenesis and survive, whereas WT mice develop CM and die. Compared with WT mice, mice lacking IL-4Rα in CD11c ⁺ or CD8α ⁺ DCs showed reduced inflammatory responses leading to decreased Th1 and cytotoxic CD8 ⁺ T cell responses, lower infiltration of CD8 ⁺ T cells to the brain, and negligible brain pathology. The novel results presented here reveal a paradoxical role of IL-4Rα signaling in CM pathogenesis that promotes CD8α ⁺ DC-mediated inflammatory responses that generate damaging Th1 and cytotoxic CD8 ⁺ T cell responses.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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