LIPID IMMUNITY · Regulation of lipid-mediated immunity in the intestine

Regulation of lipid-mediated immunity in the intestine

The current project titled Regulation of lipid-mediated immunity in the intestine aimed to explore the mechanisms regulating lipid-mediated immunity in the intestine. This tissue, in mammals, has a unique environment colonized by a highly complex mixture of microorganisms that contribute to the establishment of tissue homeostasis. Both, the microbiota and the host, establish mutual relationships that comprise, among other contributors, the intestinal immune system. Several evidences propose that the dysregulation of the intestinal immune system or the alteration in the commensal bacteria populations can lead to inflammatory and autoimmune diseases development, such as inflammatory bowel disease (IBD). In the last decades, IBD has become a global disease with accelerating incidence in newly industrialised countries (1). Data reviewed in December 2017 by Kaplan et al. highlight the need for research into prevention of this complex and costly disease. In this context, understanding the immune mechanisms involved in the pathology of this disease is crucial for its prevention and for the development of efficient therapies. It is known that interactions between immune system and commensal bacteria are complex and involved several immune cell types. One of these cell types is the population called innate lymphoid cells (ILCs) which comprise several families of cells that can be classified into three groups: ILC type 1 (ILC1), ILC2 and ILC3. Given their functions and location, ILCs have been considered as orchestrators of immune defences at mucosal surfaces (2). Lately, it has been described a novel function for ILCs as antigen presenting cells (APCs) through MHC-II-dependent presentation of commensal-derived antigens (3-7). Both ILC2 and ILC3 populations are able to internalize and present peptide antigens on MHC-II and control T cell responses (3-7). Nonetheless, in addition of source of protein antigens, commensal bacteria are a source of lipids capable to activate the lipid-reactive cells named natural killer T (NKT) cells (8,9). NKT cells, through TCR recognition of self- or commensal-derived lipids presented by CD1d, contribute to establish immune homeostasis and to anti-microbial, anti-tumour and autoimmune responses (10,11). Despite increasing data during the last decades, how commensal lipids are handled by immune cells, the contribution of different APCs to lipid presentation, and their effects on mucosal NKT cells remain poorly understood. Taking this into consideration, this project has focussed in understanding the mechanisms controlling lipid-mediated immunity by examining the ILC-NKT cell crosstalk. Specific objectives include: the characterization of CD1d expression, intracellular trafficking and lipid presentation capacity of ILC3s (Aim 1); as well as the study of the role of ILC3s on lipid-mediated immunity (Aim 2). As a result of the progress of the project, it was found that NKT cell-APCs crosstalk is a key mechanism for the regulation of intestinal homeostasis. Specifically, a previously unknown role for ILC3s on CD1d-dependent immunity was discovered. 1. Ng et al. The Lancet, 2018; 2. Artis et al. Nature, 2015; 3. Hepworth et al. Nature, 2013; 4. Hepworth et al. Science, 2015; 5. Oliphant et al. Immunity, 2014; 6. von Burg et al. PNAS, 2014; 7. Mirchandani et al. J Immunol, 2014; 8. An et al. Cell, 2014; 9. Wieland Brown et al. PLoS Biol, 2013; 10. Brennan et al., Nat Rev Immunol, 2013; 11. Salio et al., Annu Rev Immunol, 2014.

Data: CORDIS, © European Union