Antigen presentation plays a crucial role in initiating T cell-mediated adaptive immunity during disease progression, including viral infections and autoimmune diseases.Peptides are the most well characterised antigens presented to receptors on T cells (TCRs) via antigen presenting molecules known as major histocompatibility complex (MHC) proteins. The CD1 family of proteins are MHC-like proteins that present lipid antigens to T cells, and consists of 5 isoforms in humans. One member, CD1c, can present microbial lipid-based antigens from Mycobacterium tuberculosis (Mtb) in protective immunity, as well as self-phospholipids and acylglycerides that are recognised by autoreactive T cells.
Gangliosides are a class of sphingolipids enriched in the brain and nerve tissues, with studies showing that self-ganglioside presentation by CD1c to T cells play an aberrant role in mediating autoimmune disorders such as multiple sclerosis (MS). However, the molecular mechanisms that mediate this mode of activation in autoimmunity remain unknown. To answer this, we determined the crystal structure of CD1c in complex with a branched ganglioside, GD1a, by first producing CD1c recombinantly and loading GD1a into the CD1c antigen binding cleft in vitro. The two fatty acid tails of GD1a are anchored in F’ pockets with the ganglioside head group protruding out of G’ portal. Here, as opposed to standard lipid presentation by other CD1 members such as CD1d, where the branched headgroup is presented upwards towards the typical TCR recognition site, the ganglioside headgroup is presented uniquely sideways, representing a novel mechanism of antigen presentation. In summary we demonstrated, for the first time, the mechanisms of branched ganglioside presentation by CD1c. Future work will investigate CD1c-ganglioside autoreactive T cell receptor repertoire in healthy donor and patient with disease of interest.