CD8+ T cell recognition of unusual and unnatural peptide epitopes

While attempting to generate tumour specific T cell clones from leukaemia patients, we isolated a CD8+ T cell clone (6C5) with the capacity to recognize a t-butyl modified peptide (LLSY(3-tBu)FGTPT) presented by HLA-A*0201. This unusual and unnatural epitope is a poor binder to HLA-A*0201 and was likely created as a by-product of FMOC peptide synthesis. Since this epitope does not occur in nature, we sought to understand how the structural features of the LLSY(3-tBu)FGTPT/HLA-A*0201 complex could contribute to immunogenicity. We demonstrated that 6C5 T cells were specific for the type of chemical modification on peptides, and by using peptide libraries showed that 6C5 recognized several peptides derived from self-proteins. These peptides were dissimilar in sequence to LLSY(3-tBu)FGTPT but were more potent at inducing T cell function. Structural studies of three different peptide/HLA-A*0201 complexes are ongoing to determine how peptide structure can contribute to this cross-reactivity. Overall our studies show that chemical modification of peptides can influence immunogenicity but can also generate T cells with unexpected specificities.