Biology subjects

Perona-Wright, G.

Publications and source records attributed to Perona-Wright, G..

6 recordsLinked to original sources

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↗

bioRxiv2023

A PD-1-ST2 axis controls Th2 effector function in tissue via a metabolic checkpoint

Type 2 immune responses characterise both helminth infections and atopic disease such as allergy or asthma, but a better understanding of the mechanisms that regulate these responses is key to improving therapeutic and vaccination strategies. Immuno-metabolic studies over the last two decades have suggested T cell activation broadly requires rapid increases in glycolysis and oxidative phosphorylation. In contrast, we show that CD4+ T helper 2 (Th2) cells activated in vivo, using models of helminth infection, do not acquire a glycolytic metabolism. Instead, we show that Th2 cells solely increase their oxidative metabolism, associated with increased fatty acid uptake. Rather than contributing directly to effector function, our data reveal that Th2 cells switch to fatty acid oxidation downstream of PD-1 signalling to promote expression of the IL-33 receptor (ST2). These data provide insight into the spatial regulation of T cell metabolism, and suggest that PD-1 blockade therapies may be effective in Th2 disorders.

immunology↗

bioRxiv2022

Interleukin-17 drives sex-dependent weight loss and changes in feeding behaviour during Trypanosoma brucei infection

In the skin, Trypanosoma brucei colonises the subcutaneous white adipose tissue (scWAT) and harbours a pool of parasites that are proposed to be competent for forward transmission. The interaction between parasites, adipose tissue, and the local immune system is likely to drive the adipose tissue wasting and weight loss observed in cattle and humans infected with T. brucei. However, mechanistically, the events leading to scWAT wasting are not fully understood. Here, using several complementary approaches, including mass cytometry by time of flight, bulk and single cell transcriptomics, and in vivo genetic models, we found that T. brucei infection drives local expansion of several IL-17A-producing cells in the murine WAT, including TH17 and V{gamma}6+ T cells. We also found that global IL-17 deficiency, or mice lacking IL-17 receptor expression exclusively in adipocytes, were protected from infection-induced WAT wasting and weight loss. Unexpectedly, we found that abrogation of IL-17 signalling in adipocytes results in a significant accumulation of Dpp4+ Pi16+ interstitial preadipocytes and a higher burden of extravascular parasites in the WAT, highlighting a critical role for IL-17 signalling in controlling preadipocyte fate, scWAT tissue dynamics, and local parasite burden. Taken together, our study highlights the central role of adipocyte IL-17 signalling in controlling WAT responses to infection, suggesting that adipocytes are a critical coordinator of the tissue dynamics and immune responses to T. brucei infection.

immunology↗

bioRxiv2021

Tissue-based IL-10 signalling in helminth infection limits IFNγ expression and promotes the intestinal Th2 response

Type 2 immunity is activated in response to both allergens and helminth infection. It can be detrimental or beneficial, and there is a pressing need to better understand its regulation. The immunosuppressive cytokine IL-10 is known as a T helper 2 (Th2) effector molecule, but it is currently unclear whether IL-10 dampens or promotes Th2 differentiation during infection. Here we show that helminth infection in mice elicits IL-10 expression in both the intestinal lamina propria and the draining mesenteric lymph node, with higher expression in the infected tissue. In vitro, exogenous IL-10 enhanced Th2 differentiation in isolated CD4+ T cells, increasing expression of GATA3 and production of IL-5 and IL-13. The ability of IL-10 to amplify the Th2 response coincided with its suppression of IFN{gamma} expression and, in vivo, we found that, in intestinal helminth infection, IL-10 receptor expression was higher on Th1 cells in the small intestine than on Th2 cells in the same tissue, or on any Th cell in the draining lymph node. In vivo blockade of IL-10 signalling during helminth infection resulted in an expansion of IFN{gamma}+ and Tbet+ Th1 cells in the small intestine and caused a coincident decrease in IL-13, IL-5 and GATA3 expression by intestinal T cells. Together our data indicate that IL-10 signalling promotes Th2 differentiation during helminth infection at least in part by regulating competing Th1 cells in the infected tissue.

immunology↗

bioRxiv2020

Recruited macrophages that colonise the post-inflammatory peritoneal niche convert into functionally divergent resident cells

Inflammation generally leads to substantial recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages remains unclear. We compared the normal fate of inflammation-elicited macrophages in the peritoneal cavity with their potential under non-inflamed conditions and in the absence of established resident macrophages. Following mild inflammation, elicited macrophages persisted for at least 5 months but failed to fully assume a GATA6hi resident identity due to the presence of enduring resident cells. In contrast, severe inflammation resulted in ablation of resident macrophages and a protracted phase wherein the cavity was incapable of sustaining a resident phenotype, yet ultimately elicited cells acquired a mature GATA6hi identity. Elicited macrophages also exhibited divergent features resulting from inflammation-driven alterations to the peritoneal cavity micro-environment and environment-independent features related to origin and time-of-residency. Critically, one environment-dependent feature of inflammation-elicited macrophages irrespective of severity of inflammation was a failure to produce the chemokine CXCL13, which correlated with a progressive loss in accumulation of peritoneal B1 cells post-inflammation. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages appears largely regulated by environment, changes in which result in long-term alteration in function of the peritoneal macrophage compartment post-inflammation.

immunology↗

bioRxiv2019

Isolation and functional characterisation of lamina propria leukocytes from helminth-infected, murine small intestine

The use of helminth infections as tools to understand the type 2 immune response is a well-established technique and important to many areas of immunological research. The phenotype and function of immune cell populations at the site of infection is a key determinant of pathogen clearance. However, infections with helminths such as the murine nematode Heligomosmoides polygryrus cause increased mucus production and thickening of the intestinal wall, which can result in extensive cell death when isolating and analysing cells from the lamina propria (LP). Populations of larger immune cells such as macrophages and dendritic cells are often trapped within mucus or dying tissues. Here we describe an optimised protocol for isolating LP leukocytes from the small intestine of H.polygyrus -infected mice, and we demonstrate phenotypic and functional identification of myeloid and CD4+ T cell subsets using cytokine staining and flow cytometry. Our protocol may provide a useful experimental method for the immunological analysis of the affected tissue site during helminth infections.

immunology↗