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Nature Immunology 8, 388–397 (1 April 2007) | doi:10.1038/ni1446

Alloreactive T cells respond specifically to multiple distinct peptide-MHC complexes

Nathan J Felix , David L Donermeyer , Stephen Horvath , James J Walters , Michael L Gross , Anish Suri & Paul M Allen

The molecular basis underlying the specificity of alloreactive T cells for peptide–major histocompatibility complex ligands has been elusive. Here we describe a screen of 60 I-Ek-alloreactive T cells and 83 naturally processed peptides that identified 9 reactive T cells. Three of the T cells responded to multiple, distinct peptides that shared no sequence homology. These T cells recognized each peptide–major histocompatibility complex ligand specifically and used a distinct constellation of I-Ek contact residues for each interaction. Our studies show that alloreactive T cells have a 'germline-encoded' capacity to recognize multiple, distinct ligands and thus show 'polyspecificity', not degeneracy. Our findings help to explain the high frequency of alloreactive T cells and provide insight into the nature of T cell specificity.