IL36γ signaling promotes mammalian anti-tick immunity.

Ticks, like Ixodes scapularis, can parasitize a diverse array of vertebrates, favoring natural hosts but feeding opportunistically on others. Natural hosts, as well as permissive hosts such as laboratory mice, tolerate repeated infestations, while many incidental hosts may acquire anti-tick immunity, as first described in guinea pigs. We show that tick-immune guinea pigs display altered dermal cytology and a distinct transcriptome, predominantly upregulating the IL36γ cytokine. Interference with IL36γ signaling, via gene knockdown, chemical inhibition, or its natural antagonist IL36RN, reversed anti-tick immunity in guinea pigs. Conversely, genome engineering to silence IL36RN in C3H mice, representing a permissive host, disrupted tick engorgement, interfering with the transmission of Lyme disease pathogens. These findings firmly establish IL36γ as a central mediator of protective anti-tick immunity involving I. scapularis in mammalian hosts and support future strategies to interfere with tick-transmitted infections.