CD1 and MR1 recognition by human γδ T cells

The two main T cell lineages, alpha beta and gamma delta T cells, play a central role in immunity. Unlike alpha beta T cells that recognize antigens bound to the Major Histocompatibility Complex (MHC) or MHC class I-like antigen-presenting molecules, the ligands for gamma delta T cell receptors (TCRs) are much more diverse. However, it is now clear that gamma delta TCRs can also recognize MHC class I-like molecules, including CD1b, CD1c, CD1d and the MHC class I-related protein 1 (MR1). Yet, our understanding at the molecular level of gamma delta T cell immunity to CD1 and MR1 is still very limited. Here, we discuss new molecular paradigms underpinning gamma delta TCRs recognition of antigens, antigen-presenting molecules or both. The recent discovery of recognition of MR1 by a gamma delta TCR at a position located underneath the antigen display platform reinforces the view that gamma delta TCRs can approach their ligands from many directions, unlike alpha beta TCRs that bind MHC, CD1 and MR1 targets in an aligned, end to end fashion.