Periodic Reporting for period 1 - LIPID IMMUNITY (Regulation of lipid-mediated immunity in the intestine)
Reporting period: 2016-03-01 to 2018-02-28
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.
Overall, our experiments demonstrate that ILC3s express CD1d, have the capacity to internalise lipid antigens and can mediate NKT cell activation in vitro and in vivo. These functions could be particularly relevant at mucosal sites, where has been proposed that ILC3s play a central role in the anatomical containment of commensals as well as that NKT cells and CD1d expression regulate mucosal homeostasis.
Data obtained has resulted in 2 peer-reviewed publications:
• CD1d-mediated activation of group 3 innate lymphoid cells drives IL-22 production. Jimeno et al., EMBO Rep, 2017 Jan,18:39-47.
• CD11d-mediated lipid presentation by CD11c+ cells regulate intestinal homeostasis. Saez de Guinoa, Jimeno et al., EMBO J, 2018, pii:e97537.
Moreover, data were presented in 2 research conferences:
• British Society for Immunology/NVVI 2016 Congress (Liverpool, United Kingdom): December 2016
• CD1-MR1 2017 Congress (Napa, California): November 2017