T cells play a critical role in adaptive immunity, mediated by receptors on the surface of T cell (TCR) that recognise antigens presented by antigen presenting molecules. Studies on T cell immunity are centred on classical major histocompatibility complex (MHC) that present peptides to TCRs. However, non-classical antigenic molecules such as lipids can a be presented by antigen presenting proteins CD1s, which in comparison to peptide-MHC, the mechanisms of CD1 proteins presenting antigenic lipids to TCRs remain largely unknown.
Compared to peptide-MHC, CD1s are non- polymorphic, as such, the mechanisms of T cell activation by CD1 proteins can be broadly applicable to all humans. CD1b, which is well-known for presenting lipids from the Mycobacterium tuberculosis cell wall (1), has recently been shown to play a role in autoimmunity, such as in multiple sclerosis, cellular stress, and cancer. However, the molecular mechanisms of lipid presentation by CD1b, and mechanisms of modulating autoimmunity, largely remain unexplored.
Significant structural studies into the presentation of self-phospholipids by CD1b have previously been conducted, however mechanisms of self-ganglioside presentation, which include ganglioside-monosialic acid (GM1) found to induce T cell mediated autoimmune responses in multiple sclerosis (2), remain unknown. To characterise this, a panel of gangliosides previously identified as CD1 antigens were manually loaded into CD1b in vitro, and their structures were determined via x-ray crystallography. The ganglioside sphingosine and fatty acid tails are sequestered into the C’ and A’ portals of CD1b, respectively, while the ganglioside head group is positioned above the CD1b surface. CD1b presents gangliosides and phospholipids in a similar manner, however ganglioside head groups are distinctly larger and therefore protrude further above the CD1b surface than phospholipids. These findings provide novel molecular insights into the mechanism of antigenic lipid presentation by CD1b, and led to future understanding of their role in immune activation.