Biology subjects

Maloy, K. J.

Publications and source records attributed to Maloy, K. J..

3 recordsLinked to original sources

bioRxiv2025

The murine intestinal pathobiont Helicobacter hepaticus attenuates DSS colitis in a CD4+ T cell-dependent manner

The host immune system is fundamentally shaped by its resident microbiota; however, much remains unknown about how individual microbial species contribute to health and disease. Helicobacter hepaticus (Hh) is a member of the murine intestinal microbiota associated with colitis in immunodeficient mice, despite driving dominant immune regulatory responses in normal hosts which allow colonization without pathology. However, whether this colonization influences intestinal immune homeostasis more widely remains unexplored. Here, we report that Hh colonization confers a disease protective effect on DSS colitis, attenuating intestinal inflammation and other disease parameters. Disease attenuation required persistent colonization and was dependent on host CD4+ T cells. We further show that Hh colonization promotes a conserved anti-inflammatory transcriptional programme across several effector and regulatory intestinal CD4+ T cell subsets. Thus, although persistent stimulation of host immune responses allows the host to tolerate pathobionts like Hh, this is compensated by the promotion of tissue-protective immunological conditioning.

immunology↗

bioRxiv2023

MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses

Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4+ T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T cell responses during intestinal inflammation.

immunology↗

bioRxiv2021

Novel gut pathobionts confound results in a widely used mouse model of human inflammatory disease

The mammalian gut microbiota consists of hundreds of anaerobic bacterial species that shape intestinal homeostasis and influence host immune responses. Although the causal roles of specific human gut bacterial species in health and disease are emerging, the role of indigenous gut bacteria in driving immunophenotypic variability in mouse models of human disease remains poorly understood. We performed a large-scale experiment using 579 laboratory mice designed to identify and validate the causes of disease variability in the widely used dextran sulphate sodium (DSS) mouse model of inflammatory bowel disease. Using microbiome analysis, coupled with machine learning and targeted anaerobic culturing, we identified and isolated the novel gut pathobiont species Duncaniella muricolitica and Alistipes okayasuensis and fulfilled Kochs postulates in mice to show that each pathobiont exerts dominant effects in the DSS model leading to variable treatment responses. We show these pathobiont species are common, but not ubiquitous, in mouse facilities around the world, raising experimental design opportunities for improved mouse models of human intestinal diseases.

microbiology↗