Innate lymphoid cells (ILCs) are a heterogeneous family of immune regulators that protect against mucosal pathogens but can also promote intestinal pathology. Although the plasticity between ILCs populations has been described, the role of mucosal pathogens in inducing ILC conversion leading to intestinal pathology remains unclear. Here we demonstrate that IFNγ-producing ILCs are responsible for promoting intestinal pathology in a mouse model of enterocolitis caused by Campylobacter jejuni , a common human enteric pathogen. Phenotypic analysis revealed a distinct population of IFNγ-producing NK1.1 − T-bet + ILCs that accumulated in the intestine of C. jejuni -infected mice. Adoptive transfer experiments demonstrated their capacity to promote intestinal pathology. Inactivation of T-bet in NKp46 + ILCs ameliorated disease. Transcriptome analysis and cell-fate mapping experiments revealed that IFNγ-producing NK1.1 − ILCs correspond to ILC1 profile and develop from RORγt + progenitors. Collectively, we identified a distinct population of NK1.1 − ex-ILC3s that promotes intestinal pathology through IFNγ production in response to C. jejuni infection.

Human pathogen Campylobacter jejuni is a significant risk factor for the development of long-term intestinal dysfunction although the cellular and molecular mechanisms remain scantily defined. IL-23 is an emerging therapeutic target for the treatment of inflammatory intestinal diseases, however its role in C. jejuni-driven intestinal pathology is not fully understood. IL-10 deficient mice represent a robust model to study the pathogenesis of C. jejuni infection because C. jejuni infection of mice lacking IL-10 results in symptoms and pathology that resemble human campylobacteriosis. To determine the role of IL-23 in C. jejuni-driven intestinal inflammation, we studied the disease pathogenesis in IL-23-/- mice with inhibited IL-10Rα signaling. These mice exhibited reduced intestinal pathology independent from bacterial clearance. Further, levels of IFNγ, IL-17, IL-22, TNF, and IL-6 were reduced and associated with reduced accumulation of neutrophils, monocytes and macrophages in the colon. Flow cytometry analysis revealed reduced production of IL-17 and IFNγ by group 1 and 3 innate lymphoid cells. Thus, our data suggest that IL-23 contributes to intestinal inflammation in C. jejuni infected mice by promoting IL-17 and IFNγ production by innate lymphoid cells.

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