Lipids hide or step aside for CD1-autoreactive T cell receptors

Abstract

Peptide and lipid antigens are presented to T cells when bound to MHC or CD1 proteins, respectively. The general paradigm of T cell antigen recognition is that T cell receptors (TCRs) co-recognize an epitope comprised of the antigen and antigen presenting molecule. Here we review the latest studies in which T cells operate outside the co-recognition paradigm: TCRs can broadly contact CD1 itself, but not the carried lipid. The essential structural feature in these new mechanisms is a large 'antigen free' zone on the outer surface of certain antigen presenting molecules. Whereas peptides dominate the exposed surface of MHC-peptide complexes, all human CD1 proteins have a closed, antigen-free surface, which is known as the A' roof. These new structural models help to interpret recent biological studies of CD1 autoreactive T cells in vivo, which have now been broadly observed in studies on TCR-transgenic mice, healthy humans and patients with autoimmune disease.

Figure 1

Buried Ligand and Left-Right Mismatch models for autoreactive TCRs are based on recently solved ternary CD1-lipid-TCR structures

Figure 2. The Exposed Surfaces of MHC-peptide and CD1-Lipid complexes

Peptides are broadly exposed across most of the MHC I platform and across the entire MHC II platform. Idealized TCR footprints (black ovals, shown to scale) are difficult to place on MHC platforms without contacting peptide. In contrast, the A′ roof provides a large, ligand-free landing surface for TCRs on CD1 proteins. Color-coding of exposed antigen surfaces (red) shows that protruding ligands are more variable and asymmetrically positioned on CD1 platforms as compared to peptides on MHC platforms. The buried ligand mechanism describes bound lipids that fail to protrude to the surface. In the left-right mismatch mechanism, TCRs have left shifted footprints (dark grey) and the ligand (red) protrudes toward the right side of the platform.