Beyond peptides, various classes of lipids are presented for T cell surveillance via the CD1 family. In humans, there are four non-polymorphic members of the CD1 family (CD1a, CD1b, CD1c, CD1d) that present lipids to T cells in response to bacterial infection and cancers, or leading to aberrant autoimmune responses. Similarly to T cell receptor (TCR) recognition of peptide-MHC, the broad strokes of antigen-presentation and recognition are similar between the pMHC and lipid-CD1 complexes, whereby the antigen is presented at the apex of the antigen-presenting molecule allowing the exposed loops of the TCR to directly or indirectly recognise these upward facing features end-to-end.
X-ray crystallography and structural computational methods have proven instrumental in characterising the unique individual features of each CD1 molecule, as well as the molecular mechanisms of lipid size/species preferences and lipid antigen display, as defined by an in-depth standardised characterisation of CD1 plasticity, lipid size preferences, and universal cleft volume calculations across >60 crystal structures [1]. Further, we have defined models of lipid antigen presentation to TCRs, characterising mechanisms of display by cellular and bacterial lipids by each CD1, with crystal structures defining TCR recognition by either co-recognition or lipid independent models of docking [2-3] that differ from mechanisms of pMHC reactive TCRs. Taken together, this universal framework will guide the characterisation of future agonistic or antagonistic lipids for T cell immune regulation.
This structural data can be translated into the generation of novel agonistic or antagonistic therapeutics that target the CD1-lipid-TCR axis. To date, we have utilised these molecular models in the development of synthetic lipid antigens that specifically enhance CD8+ T responses against mycobacterial infected cells [4], or block autoreactive T cell responses in autoimmune contact dermatitis. Further exploration of the molecular mechanisms surrounding CD1 presentation of lipid antigens in disease will aid in establishing the key models of lipid-reactive T cell responses, thus permitting development of therapeutics that target the CD1-TCR axis of human immunity.