Campylobacter infection promotes IFNγ-dependent intestinal pathology via ILC3 to ILC1 conversion

Abstract

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.

IL-23 Contributes to Campylobacter jejuni-Induced Intestinal Pathology via Promoting IL-17 and IFNγ Responses by Innate Lymphoid Cells

“…We found a marked reduction of IFNγ-producing ILCs but not NK or T cells in the colon of IL-23 -/- mice on day 10 after C. jejuni infection ( Figures 6B, C ). aIL-10Rα antibody treatment in uninfected mice did not affect the number of IFNγ-producing ILCs and T cells in the colon ( Supplementary Figures 3A, B ), in agreement with published report ( 44 ). In contrast to colon, we did not find difference in IFNγ production by ILCs or T cells in MLN between WT and IL-23 -/- infected mice ( Supplementary Figures 3C–F ).…”

“…These data suggest that both ILCs and T cells contribute to IL-23 dependent IL-17-production during C. jejuni infection. The major producers of IFNg during C. jejuni infection are T cells, ILCs and NK cells (35,44). Our data suggest that IL-23 -/mice display reduced IFNg expression compared to WT mice ( Figure 6A).…”

“…Recently it has been shown that both IFNγ and IL-17, signature cytokines of Th1 and Th17 responses, respectively, contribute to C. jejuni -induced pathology ( 35 , 43 ). Depletion of either IFNγ or IL-17 or both during C. jejuni infection significantly decreased inflammation and pathology ( 35 , 44 ). We showed that colonic IL-17 expression was decreased in IL-23 -/- mice compared to WT mice ( Figure 5A ).…”

“…The major producers of IFNγ during C. jejuni infection are T cells, ILCs and NK cells ( 35 , 44 ). Our data suggest that IL-23 -/- mice display reduced IFNγ expression compared to WT mice ( Figure 6A ).…”

“…Surprisingly, we found that genetic ablation of IL-23 resulted in reduction of IFNγ-producing ILCs but not T cells during C. jejuni infection suggesting that ILCs can contribute to colitis development by IFNγ production during early stages of infection. Additionally, our recent data indicated that inactivation of T-bet in NKp46 + ILCs reduced intestinal pathology highlighting the pathogenic role of IFNγ + ILCs during early stages of infection ( 44 ). A previous study showed that CD4 + T cells in IL-10 -/- mice produced similar IFNγ levels compared to CD4 + T cells in IL-23 -/- IL-10 -/- mice in spontaneous model of colitis ( 52 ), indicating normal Th1 response in IL-23- and IL-10-deficient environment.…”