With palates so delicate they put food critics to shame, T cell receptors distinguish tiny bumps in molecular shape, report Archbold et al. on page 209.
Although close members of the HLA-B44 family differ by a single amino acid, they aren't interchangeable. Mismatches of HLA-B*4402 and B*4403 lead to transplant rejection. And people with B*4405 generate stronger CD8+ T cell responses against Epstein-Barr virus (EBV)than do people with either B*4402 or B*4403. Few HLA molecules have been crystallized along with their corresponding T cell receptors (TCR), so the physical basis for picky T cell preference is largely unknown.
Archbold et al. now show how just one amino acid, buried within the antigen-binding region of B*4402, B*4403, and B*4405, indirectly alters T cell recognition. Using an EBV epitope as a model, the authors found that B*4405 allowed the peptide more room to wiggle at the binding site than did B*4402 or B*4403. And that extra flexibility allowed the TCR to further change the peptide shape upon binding, allowing it to grasp onto the peptide-HLA complex more tenaciously. As a result, T cells had a 10-fold higher affinity for the peptide bound to B*4405 than to the other B44 alleles.
Therefore it wasn't the HLA polymorphism itself that altered the T cell recognition, but rather the slight shape change it caused in the bound peptide. This indirect effect probably extends to other “micropolymorphic” HLA alleles beyond the B44 family, say the authors.