Myeloid-derived IL-33 drives γδ T cell-dependent resistance against cutaneous infection by Strongyloides ratti.

Interleukin 33 (IL-33) is a pleiotropic cytokine released from diverse cell types that regulate both pro- and anti-inflammatory responses during pathogen infection. However, it remains unclear whether IL-33 controls key aspects of cutaneous immunity against skin-penetrating parasites. In this study, mice percutaneously infected with the parasitic helminth Strongyloides ratti were investigated to understand mechanisms of anamnestic immunity at the skin barrier. Surprisingly, mice lacking the Type 2 transcription factor STAT6 (signal transducer and activator of transcription 6) had no defects in secondary resistance to infection, whereas IL-33 gene deficiency or local blockade of IL-33 receptor (ST2) signaling abrogated host resistance. Depletion of CD4+ T cells or type 2 innate lymphoid cells had only a moderate impact on protection, but the loss of γδ T cells completely ablated cutaneous immunity against rechallenge. We identified a CD62Lhi IL-33 receptor (ST2)-expressing γδ T cell population that accumulated in the skin of protected mice that was dependent upon IL-33 expression in myeloid lineage antigen-presenting cells. This work suggests a previously unrecognized mechanism wherein noncanonical type 2 immunity operates through myeloid antigen-presenting cells and skin γδ T cells to adaptively repel skin-penetrating helminth larvae.