Title: Unravelling new immune-regulatory switches by manipulating cellular cholesterol metabolism in humans
Funder: The Academy of Medical Sciences

Abstract: There are two key steps in the generation of a protective immune response: the activation of immune cells to promote inflammation and the elimination of the pathogen, followed by the resolution of the response once the pathogen is controlled, preventing over-reactivity and tissue damage. This resolution phase is an active process, and it is paramount to restoring immune homeostasis and to maintaining health. My work has discovered that cellular cholesterol metabolism controls the switch between the effector and resolution phases by regulating the production of interleukin (IL)-10, a potent anti-inflammatory cytokine, through a mechanism still unknown. Capitalising on this finding, in this proposal I aim at unravelling the molecular and cellular mechanisms that integrate cholesterol metabolism with the effector immune response, with a focus on human CD4+ T cells. I will use ex vivo and in vitro experimental approaches to understand this relationship at the cellular and systemic level. I hypothesise that correct cholesterol metabolism homeostasis is a requirement for the resolution phase of the immune response to happen, by regulating IL-10 expression in CD4+ T cells. This is a new regulatory step that can be exploited where manipulation of immune homeostasis is desirable, from chronic inflammatory and metabolic disease to cancer and infection. My project is structured around 2 aims: 1. Investigating novel molecular mechanisms that integrate immunological cues and cholesterol metabolism in health. 2. Investigating the connection between systemic and cellular cholesterol metabolism and immune response.

Lay abstract: Upon infection or danger, the human body reacts by activating the immune system, that will trigger a response against the pathogen and clear it from the body. After this effector phase, the response will shut down, returning to a basal situation ready for the next challenge. This resolution process is key to maintain health. CD4+ T cells are immune cells that orchestrate this response and secrete a specific factor called interleukin-10 (IL-10) to promote resolution. I have discovered that IL-10 is regulated by cholesterol metabolism. All the cells in the body can produce cholesterol, that is very important for them to function correctly. However, in CD4+ T cells, the cholesterol pathway seems to have an extra function, that is regulate the expression of IL-10. In this project we want to explore this new finding further: we want to identify precisely how cholesterol metabolism can perform this regulatory function. Moreover, we want to investigate whether these signals are altered in patients with diseases of the immune system (like rheumatoid arthritis) or diseases of the cholesterol pathway (like hypercholesterolemia). To achieve this, we will extract cells from the blood of individuals and test these cells in the laboratory using new technologies that allow us to define the cells in a very precise way. We will identify the signals that make them produce IL-10 and that are controlled by cholesterol metabolism. Then we will study if these signals are different in CD4+ T cells from tissue and blood donated from patients.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE