Rossjohn Laboratory

The central interaction in T cell immunity involves two steps: loading antigens (Ags) onto the surface of professional antigen-presenting cells (APCs) and T cell receptor (TCRs) recognition of the formed Ag-APC complexes. Following this, an intracellular signalling cascade is triggered, leading to T cell activation. An unconventional T cell subset termed Natural Killer T (NKT) cells could recognise lipid-based Ags upon presentation by the non-polymorphic MHC class 1-like molecule CD1d. Little is known about the spectrum of lipid Ags presented by CD1d and their mechanism of activation of NKT cells, as this is crucial to manoeuvre their biological outcomes. Notably, NKT cells have great implications for autoimmunity, microbial immunity and mucosal immunity. Emerging evidence suggests that the gut microbiota comprising a large number of symbiotic microbes plays a crucial role in shaping the mammalian host’s T cell-mediated immune responses in the context of NKT cells. Of note, Bacteroides fragilis, a predominant bacterium, present in microbiota produces sphingolipids such as a-galactosylceramides, known as ‘BfaGCs’, that possess unique immunomodulatory properties. Thus, an interplay exists between symbiotic bacteria and the immune cells that influence immune regulation in the host.

Our team focuses on this unchartered area of T cell immunity driven by human gut microbiota-produced lipids. We aim to address a few major fundamental questions: (1) What is the breadth of diverse CD1d-specific lipid Ags produced by the gut microbiota? (2) What molecular factors govern the presentation of these produced lipid Ags? (3) How are these lipid Ags recognised by TCRs and modulate T cell immunity? Using multidisciplinary approaches including molecular biology, protein chemistry, X-ray crystallography, cellular immunology and various biophysical techniques, we like to address the role of lipid Ags in T cell immunity towards the ‘Microbiome-NKT’ axis.