Antigen-presenting cells (APCs) in the gut are apt at oral tolerance establishment at steady state and immunity after infection; complex tasks in an environment exposed to the inflammatory burden of the microbiota. Here we show an unanticipated division of labor among APCs for the establishment of oral tolerance. Chemokine receptor CX3CR1(+) macrophages were found to take up soluble fed antigens and quickly transfer them to CD103(+) dendritic cells (DCs). Antigen transfer occurred via a mechanism that was Connexin 43-dependent and required membrane transfer, indicating a physiological role of gap junctions in antigen presentation. Deletion of Connexin 43 in APCs affected antigen transfer and resulted in the inability of CD103(+) DCs to acquire and present antigens in vivo, to drive T regulatory cell differentiation and to induce tolerance to food antigens. This functional cooperation between intestinal phagocytes might be a mechanism to avoid the exposure of tolerogenic DCs to the intestinal microbiota.

We identified a new IDO-dependent pathway leading to acquisition of tolerogenic functions in mucosal CD103-expressing DCs, indicating IDO as a possible therapeutic target for gut disorders.

The interrelationship between IgAs and microbiota diversity is still unclear. Here we show that BALB/c mice had higher abundance and diversity of IgAs than C57BL/6 mice and that this correlated with increased microbiota diversity. We show that polyreactive IgAs mediated the entrance of non-invasive bacteria to Peyer's patches, independently of CX3CR1(+) phagocytes. This allowed the induction of bacteria-specific IgA and the establishment of a positive feedback loop of IgA production. Cohousing of mice or fecal transplantation had little or no influence on IgA production and had only partial impact on microbiota composition. Germ-free BALB/c, but not C57BL/6, mice already had polyreactive IgAs that influenced microbiota diversity and selection after colonization. Together, these data suggest that genetic predisposition to produce polyreactive IgAs has a strong impact on the generation of antigen-specific IgAs and the selection and maintenance of microbiota diversity.

Cross-presentation of antigen by dendritic cells (DCs) to CD8+ T cells is a fundamentally important mechanism in the defense against pathogens and tumors. Due to the lack of an appropriate lineage marker, cross-presenting DCs in the mouse are provisionally classified as “Batf3-IRF-8-Id2-dependent DCs” or as “CD8+ DCs” in the spleen, and as “CD103+CD11b− DCs” in the periphery. We have now generated a mAb to XCR1, a chemokine receptor which is specifically expressed on CD8+ DCs and a subpopulation of double negative DCs in the spleen. Using this antibody, we have determined that only XCR1+CD8+ (around 80% of CD8+ DCs) and their probable precursors, XCR1+CD8− DCs, efficiently take up cellular material and excel in antigen cross-presentation. In lymph nodes (LNs) and peripheral tissues, XCR1+ DCs largely, but not fully, correspond to CD103+CD11b− DCs. Most importantly, we demonstrate that XCR1+ DCs in the spleen, LNs, and peripheral tissues are dependent on the growth factor Flt3 ligand and are selectively absent in Batf3-deficient animals. These results provide evidence that expression of XCR1 throughout the body defines the Batf3-dependent lineage of DCs with a special capacity to cross-present antigen. XCR1 thus emerges as the first surface marker characterizing a DC lineage in the mouse and potentially also in the human.

Data from Mediterranean and Central European countries are urgently needed to understand whether RTW is an issue for CSs there as well and whether socio-rehabilitative interventions are required to mitigate the potential negative impact of cancer on individuals and society.