20 It is more likely that some alleles exhibit a less restrictive peptide binding while other MHC class I alleles show a more restrictive peptide binding pattern. Most MHC class I molecules have been studied in detail and peptide anchor positions have been identified. HLA-A*0201 preferentially recognizes peptides with the amino acids leucine

or methionine at position Pirfenidone 2 and valine or leucine at the C-terminus.24 Only two out of 17 epitopes showed ‘correct’ anchor residues; others had either one ‘correct’ anchor residue or residues with similar hydrophobic groups at these positions. Other peptides, such as SQIMYNYPA (TB10.42–10), shared almost none of the previously reported preferred residues, but they strongly stabilized the HLA-A*0201 monomer, sufficient for tetramer production. For many of the TB10.4 peptides, we could identify Everolimus solubility dmso extensive ‘cross-binding’ to different MHC class I molecules. MHC molecules have been divided into supertypes based on similar binding preferences for peptides.25 Some of the cross-binding could be a result of the fact that the alleles belong to the same supertype, or to supertypes with similar binding preferences. However, the majority of the peptides identified in the current study bound to alleles that exhibited very different binding preferences; for example, they bound both to HLA-A and HLA-B alleles.

This observation has previously been postulated to represent an exception rather than a rule.26,27 Only recently, more systematic studies of HIV

epitopes and human papillomavirus (HPV) epitopes showed that this phenomenon may be more common.28,29 In the context of nonviral pathogens, ‘cross-binding’ has previously been reported for the Mtb protein Ag85B19 and the tumour-associated protein 5T4.20 The extensive promiscuity of peptides in their binding to different MHC class I molecules may certainly be of clinical importance considering the vast number of alleles that exist. A peptide capable of binding to Pregnenolone many different MHC class I molecules is more likely to be presented by a majority of people, a situation that could facilitate vaccine design, as fewer epitopes are needed to cover large population cohorts. While this might be positive from the perspective of vaccine design, it may also mean that a narrow focus on a few epitopes, presented by a high number of alleles to CD8+ T cells, could lead to ‘immune exhaustion’ or escape mutations. Escape mutations are common in viral epitopes but have not yet been reported for Mtb epitopes. This may be a result of the fact that the mutation rate for immunogenic Mtb proteins has been shown to be quite low;30 in addition, data comparing a comprehensive panel of Mtb isolates using genome-wide analysis are lacking at this time. In the case of TB10.4, similar epitopes from the closely related proteins TB10.3 and TB12.