A team of MRC WIMM researchers in the Cerundolo Group, led by Dr Mariolina Salio, have published research in PNAS uncovering the molecular and functional underpinnings of a class of major histocompatibility complex ligands implicated in immune system function.
Major histocompatibility complexes (MHC) are molecules found on the surfaces of T-cells, which belong to a group of immune system cells known as lymphocytes. The MHC molecules help the T-cells recognise foreign substances. MHC molecules are very polymorphic (with several different forms and types) and the T cells recognising MHC peptide complexes have a variety of T cell receptors. Subsets of T cells, known as innate-like T cells, also recognise metabolites presented by molecules similar to MHC that are present on the surface of antigen-presenting cells. MHC-like molecules are monomorphic and innate-like T cells often have relatively similar T-cell receptors. The more consistent nature of these similar molecule and receptor systems make them good candidates for cell population wide-clinical manipulation.
Dr Salio and her team highlight that there is great interest in harnessing innate-like T cells and enhancing their peptide-specific T cell responses, by activating them using cells presenting antigens the T cells recognise. To make this possible they wanted to understand the finer details of how antigens are presented so that they are recognised by innate-like T cells.
Specifically, they focussed on the innate-like T cell population known as mucosal-associated invariant T cells (MAIT cells - so named as they are found in abundance at mucosal surfaces) and MHC class I-related molecules (MR1) which present ligands to the MAIT cells. MAIT cells are very abundant in human mucosal tissues, in peripheral blood and in the liver and the antigens presented by MR1 are intermediates of vitamin B2 metabolites, produced by a variety of microbes, commensals and pathogenic.
Through in silico screening of ligands fitting the MR1 binding pocket, Dr Salio and her team identified six non-microbial MAIT cell agonists and a novel class of antagonists.
Unusually, MR1 antigen presentation at the cell surface is tightly regulated by ligand availability. While previously described MR1 ligands facilitate translocation of ER-resident MR1 to the cell surface, the researchers describe the first non-microbial ligands, DB28 and its ester analogue NV18.1, which retain MR1 in the ER in an immature ligand-receptive form and competitively inhibit stimulatory ligands. Their work provides the molecular and functional basis underpinnings of the interactions of this new class of ligands with MR1.
Previous research had revealed that MAIT cells play a protective role in microbial infections, and are implicated in cancers and inflammatory diseases including obesity, diabetes, multiple sclerosis and inflammatory bowel disease. The new agonist compounds could be the starting point for structure-activity studies aimed at designing novel ligands that drive MAIT cell-dependent Dendritic Cell and B cell maturation, hence protective adaptive immunity. The novel antagonist may prove to be a useful tool compound for in vivo modulation of undesirable MAIT cell activity, for example in autoimmunity.