Acquired resistance against skin penetration by Strongylodies rattiis dependent on IL-33 expressing APCs

Abstract

Abstract Interleukin 33 (IL-33) is an alarmin cytokine released from damaged epithelia that is essential for protection against gastrointestinal (GI) helminth (worm) infection, but whether IL-33 serves any role in cutaneous immunity against parasites remains unclear. While epithelial cells are considered the predominant source of IL-33, our recent work demonstrates that CD11c+ myeloid antigen presenting cells can express IL-33 to shape Type 2 immunity. We developed a percutaneous infection model using Strongylodies ratti, a rodent-specific GI helminth, to better understand mechanisms of host protection and the potential role for IL-33. Data show that C57BL/6 mice develop resistance to percutaneous infection upon secondary challenge, but IL-33 deficient mice lack this capacity. Surprisingly, mice with a selective IL-33 deficiency only in myeloid APC (CD11c Cre) also failed to develop secondary resistance to S. ratti, suggesting myeloid-derived IL-33 is essential for cutaneous immunity. Mechanistically, we find that loss of myeloid IL-33 impairs recruitment of gd T cells that express the IL-33 receptor ST2 and gene deficient mice that lack all gd T cells show defective protective immunity against S. ratti. Moreover, we propose that IL-33 drives a noncanonical Type 2 immunity, because mice lacking the Type 2 transcription factor STAT6 (Signal transducer and activator of transcription 6), have no defects in primary or secondary cutaneous immunity. Our work implies that myeloid APCs are a necessary source of IL-33 that drives acquired immunity against helminths, potentially through regulating gd T cell effector function(s). Ongoing studies seek to understand how myeloid APC derived IL-33 controls gd T cells to promote cutaneous immunity. NIH (R01 AI095289 and R01 GM083204) NSF GFRP