Intestinal helminth skews DC2 development towards regulatory phenotype to counter the anti-helminth immune response

Abstract

The intestinal immune system maintains a balance between active immunity needed for protection and tolerance towards harmless antigens. Dendritic cells (DCs) found in the intestinal mucosa are key to the adaptive arm of these immunoregulatory events. DCs sample antigens in the tissue and then migrate to the draining lymph nodes, where they prime the T cells that then migrate back to the tissue as effector or regulatory cells. Intestinal DC are highly heterogeneous, and it remains unclear exactly which subsets induces the different kinds of immune response, or what signalling molecules and cellular mechanisms are involved. Here, we have studied these issues usingHeligmosomoides polygyrus bakeri (Hpb)infection in mice, a model which is uniquely suited to dissecting this regulatory circuit in the gut, where it drives type 2 protective immunity at the same time as inhibiting other aspects of the immune response. Here, we characterise intestinal DC duringHpbinfection for the first time. We observed a dynamical change of intestinal DC populations throughout the course of infection that correlated with altered phenotype and function. In particular,Hpbinfection saw a rise in a population of CD103+DC2 that retained a potent ability to drive Tregs during the infection and unlike CD103-DC2, had a reduced ability to induce pro-inflammatory immune response. Furthermore, transcriptional analysis revealed that TGFβ signalling may be responsible for some of the changes observed. This was confirmedin vitro, where supplementation TGFβ orHpb-produced TGFβ mimic (TGM) replicated the immunomodulatory effects seen in DCsin vivo. Together, these results present a mechanistic explanation of how helminths such asHpbmay modulate host immune responses by altering the differentiation and function of local DCs. Furthermore, our work provides the basis for understanding immune homeostasis in the intestine at the molecular and cellular levels. Thus, this work fills out a crucial gap in our knowledge of basic biology underlining the DC decision between pro- and anti-inflammatory immune response in the central circuit of adaptive immune response.