Intestinal helminth skews dendritic cell development to counter the anti-helminth immune response

Intestinal dendritic cells (DC) orchestrate the adaptive immune response that balances protection against pathogens and tolerance towards harmless antigens. Yet, it remains largely unknown what molecular mechanisms underly this functional duality. Heligmosomoides polygyrus bakeri (Hpb) is a naturally occurring parasite in mice characterised by unique immune-evasion strategies that counter host protective immunity. Here, we utilised this unique infection environment to study mechanisms by which DC maintain the immune balance. In-depth characterisation of intestinal DC during Hpb infection revealed the emergence of distinct populations of DC that drive protective Th2 responses, versus others with immunoregulatory properties. We also identified that the skewing of intestinal DC towards immunoregulatory functions was due to TGFb signalling via endogenous sources or by Hpb-produced TGFb-mimic molecules. Thus, our results present a mechanistic explanation for Hpb's ability to modulate the adaptive immune system. Furthermore, these data offer an example of how heterogeneity within the DC compartment can determine the simultaneous generation of both pro- and anti-inflammatory immune responses. Overall design: Bulk RNA sequencing analysis of FACS-purified CD103- and CD103+ DC2 populations isolated from granuloma and non-granuloma regions at 7 days post infection with Heligmosomoides polygyrus bakeri, as well as naïve, from small intestine lamina propria. Pre-gated as live, singlets, CD3-, B220-, CD19-, CD45+, CD64-, CD11c+, MHCII+. Then two populations of DC2 identified as CD11b+CD103- and CD11b+CD103+. Each sample contains pooled RNA isolated at two individual experiments (4-5 aniamls per each experiment; 8-10 animals in total per each sequenced sample). Each sample contains RNA representative of 80-100k cells.