Defense against attaching and effacing (A/E) bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. While CD4+ and NKp46+ innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the A/E pathogen Citrobacter rodentium. We found that Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b+ cDCs, but not Batf3-dependent CD103+ cDCs, were an obligate source of IL-23 required to survive C. rodentium infection. These results provide the first demonstration of a non-redundant function of CD11b+ cDCs in response to pathogens in vivo.

Song et al. generate mice selectively lacking NKp46+ ILC3s to demonstrate that in the absence of T cells, NKp46+ILC3s are sufficient to promote inflammatory monocyte accumulation in CD40-induced colitis via production of GM-CSF. In T cell–sufficient mice, the lack of NKp46+ILC3s did not impact C. rodentium infection.

Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses against external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 cells, the transcriptional control of lineage commitment for each ILC subset is incompletely understood. Here we report that the transcription factor Runx3 was essential for normal development of ILC1 and ILC3, but not ILC2 cells. Runx3 controlled the survival of ILC1, but not ILC3 cells. Runx3 was required for the expression of RORγt and its downstream target, aryl hydrocarbon receptor, in ILC3 cells. The absence of Runx3 in ILCs exacerbated C. rodentium infections. Therefore, our data establish Runx3 as a key transcription factor for lineage-specific differentiation of ILC1 and ILC3 cells.

The early host response to pathogens is mediated by several distinct pattern recognition receptors. Cytoplasmic RNA helicases including RIG-I and MDA5 have been shown to respond to viral RNA by inducing interferon (IFN) production. Previous in vitro studies have demonstrated a direct role for MDA5 in the response to members of the Picornaviridae, Flaviviridae and Caliciviridae virus families ((+) ssRNA viruses) but not to Paramyxoviridae or Orthomyxoviridae ((−) ssRNA viruses). Contrary to these findings, we now show that MDA5 responds critically to infections caused by Paramyxoviridae in vivo. Using an established model of natural Sendai virus (SeV) infection, we demonstrate that MDA5−/− mice exhibit increased morbidity and mortality as well as severe histopathological changes in the lower airways in response to SeV. Moreover, analysis of viral propagation in the lungs of MDA5−/− mice reveals enhanced replication and a distinct distribution involving the interstitium. Though the levels of antiviral cytokines were comparable early during SeV infection, type I, II, and III IFN mRNA expression profiles were significantly decreased in MDA5−/− mice by day 5 post infection. Taken together, these findings indicate that MDA5 is indispensable for sustained expression of IFN in response to paramyxovirus infection and provide the first evidence of MDA5-dependent containment of in vivo infections caused by (−) sense RNA viruses.

Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies.DOI: http://dx.doi.org/10.7554/eLife.04494.001