Nair et al. define a key role for Irg1 in minimizing the pathological immune response associated with Mtb infection. Using Irg1−/− and Irg1fl/fl conditional mice, detailed immune cell analysis, and transcriptional profiling, their data supports a model where Irg1 expression in myeloid cell subsets tempers inflammation and controls the recruitment and infection of neutrophils during Mtb infection.

Summary CD8α+ dendritic cells (DCs) prime cytotoxic T lymphocytes during viral infections and produce interleukin-12 in response to pathogens. Although the loss of CD8α+ DCs in Batf3−/− mice increases their susceptibility to several pathogens, we observed that Batf3−/− mice exhibited enhanced resistance to the intracellular bacterium Listeria monocytogenes. In wild-type mice, Listeria organisms, initially located in the splenic marginal zone, migrated to the periarteriolar lymphoid sheath (PALS) where they grew exponentially and induced widespread lymphocyte apoptosis. In Batf3−/− mice, however, Listeria organisms remain trapped in the marginal zone, failed to traffic into the PALS, and were rapidly cleared by phagocytes. In addition, Batf3−/− mice, which lacked the normal population of hepatic CD103+ peripheral DCs, also showed protection from liver infection. These results suggest that Batf3-dependent CD8α+ and CD103+ DCs provide initial cellular entry points within the reticuloendothelial system by which Listeria establishes productive infection.

TH1 and TH17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic TH cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). TH cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here, we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40−/−) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40−/− TH1 and TH17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40−/− mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T cell pathogenicity.

The cytokine IL-10 antagonizes pathways that control () infection. Nevertheless, the impact of IL-10 during infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress expression during infection. Loss of Bhlhe40 in mice results in higher expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of in mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c cells is sufficient to cause susceptibility to Bhlhe40 represents the first transcription factor found to be essential during infection to specifically regulate expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in pathogenesis.

Lin et al. show that Bhlhe40 expression identifies encephalitogenic CD4+ T helper cells and define a pertussis toxin–IL-1–Bhlhe40 pathway active in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis.