Jakob Loschko

Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium

Using a new mouse model, the specific deletion of monocytes and macrophages reveals that, although not required to initiate immunity to Citrobacter rodentium, they contribute to the adaptive response via IL-12 secretion to induced IFN-γ+ Th1 polarization.

The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells

Summary Inflammation triggers the differentiation of Ly6Chi monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3+CD11c−MHCII+PU.1hi subset. This subset acted as a precursor for FcγRIII+PD-L2+CD209a+, GM-CSF-dependent moDCs but was distal from the DC lineage, as shown by fate-mapping experiments using Zbtb46. By contrast, Flt3−CD11c−MHCII−PU.1lo monocytes differentiated into FcγRIII+PD-L2−CD209a−iNOS+ macrophages upon microbial stimulation. Importantly, Sfpi1 haploinsufficiency genetically distinguished the precursor activities of monocytes toward moDCs or microbicidal macrophages. Indeed, Sfpi1+/− mice had reduced Flt3+CD11c−MHCII+ monocytes and GM-CSF-dependent FcγRIII+PD-L2+CD209a+ moDCs but generated iNOS+ macrophages more efficiently. Therefore, intercellular disparities of PU.1 expression within naive monocytes segregate progenitor activity for inflammatory iNOS+ macrophages or moDCs.

L-Myc expression by dendritic cells is required for optimal T-cell priming

The transcription factors c-Myc and N-Myc—encoded by Myc and Mycn, respectively—regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1gfp allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte–macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103+ conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.

Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation

Nussenzweig et al. use a novel mutant mouse lacking MHC class II expression on conventional dendritic cells (cDCs) to demonstrate the importance of cDCs in the maintenance of intestinal homeostasis.

Inducible targeting of cDCs and their subsets in vivo.

Conventional dendritic cells (cDCs) are essential immune cells linking the innate and adaptive immune system. cDC depletion in mice is an important method to study the function of these cells in vivo. Here we report an inducible in vivo system for cDC depletion in which excision of a loxP flanked Stop signal enables expression of the human diphtheria toxin receptor (DTR) under the control of Zbtb46 (zDC(lSlDTR)). cDCs can be specifically depleted by combining zDC(lSlDTR) mice with a Csf1r(Cre) driver line. In addition, we show that zDC(Cre) mice can be used to produce cDC specific conditional knockout mice (Irf8, Irf4, Notch2) which lack specific subsets of cDCs.

Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance

A secreted bacterial protein protects worms and mice from Salmonella pathogenesis. Microbes teach tolerance in the gut The trillions of microbes inhabiting our gut can greatly affect how we respond to infection, but scientists do not fully understand the molecular mechanisms shaping how different microbes interact with the host. Rangan et al. found that both worms and mice harboring Enterococcus faecium can better tolerate Salmonella infection. In both cases, tolerance requires E. faecium to express the enzyme secreted antigen A (SagA). SagA can also exert this probiotic effect when expressed by other bacteria. SagA protects worms by cleaving bacterial peptide fragments so that they can stimulate the tol-1 protein. In mice, Pedicord et al. found that SagA protects against Salmonella and Clostridium difficile pathogenesis in a manner dependent on antimicrobial peptides and multiple innate immune receptors. Commensal intestinal bacteria can prevent pathogenic infection; however, limited knowledge of the mechanisms by which individual bacterial species contribute to pathogen tolerance has restricted their potential for therapeutic application. We examined how colonization of mice with a human commensal Enterococcus faecium protects against enteric infections. We show that E. faecium improves host intestinal epithelial defense programs to limit Salmonella enterica serotype Typhimurium pathogenesis in vivo in multiple models of susceptibility. E. faecium protection is mediated by a unique peptidoglycan hydrolase, secreted antigen A (SagA), and requires epithelial expression of pattern recognition receptor components and antimicrobial peptides. Ectopic expression of SagA in nonprotective and probiotic bacteria is sufficient to enhance intestinal barrier function and confer tolerance against S. Typhimurium and Clostridium difficile pathogenesis. These studies demonstrate that specific factors from commensal bacteria can be used to improve host barrier function and limit the pathogenesis of distinct enteric infections.

Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.

Li et al. describe a novel role for IRF2, previously known as a negative regulator of type I IFN signaling, in protection of mice from lethal viral neuroinvasion by facilitating the proper localization of B cells and antibodies to the central nervous system.

Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets

Summary Visceral adipose tissue (VAT) has multiple roles in orchestrating whole-body energy homeostasis. In addition, VAT is now considered an immune site harboring an array of innate and adaptive immune cells with a direct role in immune surveillance and host defense. We report that conventional dendritic cells (cDCs) in VAT acquire a tolerogenic phenotype through upregulation of pathways involved in adipocyte differentiation. While activation of the Wnt/β-catenin pathway in cDC1 DCs induces IL-10 production, upregulation of the PPARγ pathway in cDC2 DCs directly suppresses their activation. Combined, they promote an anti-inflammatory milieu in vivo delaying the onset of obesity-induced chronic inflammation and insulin resistance. Under long-term over-nutrition, changes in adipocyte biology curtail β-catenin and PPARγ activation, contributing to VAT inflammation.