Plasticity of ILC3 in intestinal inflammation

Principle Investigator

Scientific interest within the context of the graduate college

We study the development and function of the innate immune system, with a particular emphasis on innate lymphoid cells (ILC). Our current goal is to achieve a molecular-level understanding of how the innate immune system integrates environmental cues (such as those derived from nutrients, microbiota, and circadian rhythm) to influence tissue physiology. Recent findings have uncovered increasingly complex interactions between components of the innate immune system and fundamental developmental and biological processes, pointing to previously unrecognized pathways through which immune mechanisms may be harnessed to enhance health and longevity. These insights suggest expanded roles for the immune system in regulating tissue homeostasis, morphogenesis, metabolism, regeneration, and growth. Our work is inherently interdisciplinary, bridging fields such as immunology, microbiology, epigenetics, developmental and stem cell biology, nutrition science, tumor biology, and regenerative medicine.

Project description

Group 3 Innate lymphoid cells (ILC3) are tissue-resident innate lymphocytes that are involved in immunity to infections but are also deeply integrated in the regulation of tissue function. ILC3 are crucial regulators of intestinal barrier homeostasis in both health and disease. In contrast to adaptive lymphocytes, they are constantly active and serve both as direct responders, i.e. by sensing mediators and metabolites and secreting effector cytokines, but also participate in discrete regulatory circuits with both immune and non-hematopoietic cells. However, ILC3 are highly heterogenous, and different subpopulations have markedly different phenotypes with differential expression of immune regulatory receptors and effector cytokines. Recent findings from our laboratory indicate that this heterogeneity arises due to post-developmental plasticity of ILC3 in response to changes in the tissue (micro)environment. Specifically, we have demonstrated that ILC3 are epigenetically poised for alternate cell fate decisions, resulting in subsequent changes in effector functions (manuscript in preparation). Importantly, our data suggests that this epigenetically encoded plastic potential may constitute an intrinsic switch that enable ILC3 to adapt during intestinal inflammation, as an alternative mode of defense to reestablishment of barrier integrity and homeostasis.

In a TNF-driven model of inflammatory bowel disease (IBD), we observe a transformation of the ILC3 compartment indicating that such epigenetic reprogramming is occurring. The drivers of the change of the intestinal ILC3 compartment, and the immediate and long-term consequences remain to be elucidated. We hypothesize that intestinal inflammation activates these epigenetically encoded programs in ILC3 and that the propensity for such reprogramming is further regulated by both intrinsic and extrinsic factors (e.g. cytokines, vitamins and aryl hydrocarbons).

In this proposal, we aim to investigate the epigenetic foundation of ILC3 lineage stability in the context of intestinal inflammation, whether this is causally linked to disease progression and explore if targeted intervention of ILC3 plasticity may affect disease progression and outcome.

Aim 1: Characterize the lineage stability and plasticity of ILC3 in murine models of intestinal bowel disease. We will use established protocols for epigenetic profiling of ILC3 combined with transcriptomic analysis and state of the art lineage tracing techniques to identify changes in ILC3 during intestinal inflammation.

Aim 2: Investigate the cause-and-effect relationships of ILC3 plasticity in intestinal inflammation. Using both novel and established genetic targeting of ILC3 as well as dietary interventions, we will investigate the causal relationships of ILC3 plasticity in intestinal inflammation.

Application details

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