Milling, S. W. | Search bioRxiv

bioRxiv2024

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

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 using Heligmosomoides 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 during Hpb infection 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, Hpb infection 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 TGF{beta} signalling may be responsible for some of the changes observed. This was confirmed in vitro, where supplementation TGF{beta} or Hpb-produced TGF{beta} mimic (TGM) replicated the immunomodulatory effects seen in DCs in vivo. Together, these results present a mechanistic explanation of how helminths such as Hpb may 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.

immunology↗

bioRxiv2020

Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumour growth via a mast cell-dependent pathway

The diverse community of commensal microbes that comprise the gut microbiota is known to play an integral role in human health, not least through its ability to regulate host immune responses and metabolic pathways. Alterations to the homeostasis of this community, including through the use of broad-spectrum antibiotics, have already been associated with the progression of several cancers, namely melanoma and liver. The aggressive nature of breast cancer (BrCa), largely due to its ability to metastasize early, has ranked the disease with the second highest mortality rate of all cancers globally. Yet the body of research into the complex relationship between the microbiota and BrCa is still limited. This study found that a depletion of the microbiota, through the administration of antibiotics, significantly increased the rate of primary tumour progression in mouse BrCa models. We show that antibiotic-induced microbiota disturbances lead to changes in behaviour of a relatively obscure tumour-immune cell population: mast cells. We observed increases in tumour stroma-associated mast cells in antibiotic treated animals. Moreover, inhibition of mast cell degranulation, via cromolyn, slowed tumour progression in antibiotic treated animals but not in control animals. Thus, it appears that a perturbed microbiota drives stroma-associated mast cell recruitment and activation, which in turn promotes primary tumour growth through an as yet unknown mechanism. One Sentence Summary: We show that breast cancer progression is accelerated through a unique/novel immune response involving mast cells as a result of an antibiotic induced perturbation of the gut microbiota in a mouse model.

cancer biology↗