An autoimmune TCR (left; red and yellow) sits off-center on its MHC (blue) and peptide (green) compared with a more conventional arrangement (right).


A crooked T cell receptor (TCR)–MHC interaction may result in immune responses that are similarly skewed, based on findings from Michael Hahn, Kai Wucherpfennig, and colleagues (Dana-Farber Cancer Institute, Boston, MA). The TCR in question is associated with multiple sclerosis, suggesting that protective and autoimmune T cells recognize antigens differently.

A head-on approach has been seen in protective cases, in which the TCR sits directly atop the foreign peptide/MHC complex on an antigen-presenting cell. Now, the authors present the first crystal structure of an autoimmunity-generating complex—a TCR that binds to MHC presenting the myelin basic protein (MBP) peptide.

This structure, derived from a TCR that was isolated from a multiple sclerosis patient, reveals a tilted complex in which the TCR contacted mostly the NH2-terminal portion of the MBP peptide. The hypervariable (rearranged) TCR loops created a much larger fraction of the contact surface with the MHC and peptide than in conventional arrangements. “It's the sequence diversity of TCRs that allows these unusual topologies,” says Wucherpfennig.

The CD4 coreceptor, which is required for T cell function, was thus unusually positioned. If this odd geometry limits T cell activation in the thymus, the cell might evade negative selection (the removal of autoreactive T cells) and escape to the periphery. Escapees remain harmless unless they are activated, possibly by microbial peptides with some structural similarity to MBP. This kind of activation might be more likely since the TCR recognizes a smaller-than-normal section of the peptide.


Hahn, M., et al.
Nat. Immunol.