I-EP BOUND SELF-PEPTIDES: IDENTIFICATION AND CHARACTERIZATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T cell recognition of peptide/allogeneic MHC complexes is a major cause of transplant rejection. Both the presented self-peptides and the MHC molecules are involved; however, the molecular basis for alloreactivity and the contribution of self-peptides are still poorly defined. The murine 2.102 T cell is specific for Hb(64-76)/I-Ek and is alloreactive to I-Ep. The natural self-peptide/I-Ep complex recognized by 2.102 remains unknown. In this study, we characterized the peptides which are naturally processed and presented by I-Ep, and used this information to define the binding motif for the murine I-Ep class II molecule. Interestingly, wefound that the P9 anchor residue preferred by I-Ep is quite distinct from the residues preferred by other I-E molecules, although the P1 anchor residue is conserved. A degree of specificity for the alloresponse was shown by the lack of stimulation of 2.102 T cells by 19 different identified selfpeptides. The binding motif was used to search the mouse genome for candidate 2.102 reactive allo-peptides that contain strong P1 and P9 anchor residues and possess previously identified allowable TCR contact residues. Two potential allo-peptides were identified, but only one of these peptides, G protein-coupled receptor 128, was able to stimulate 2.102 T cells. The G protein-coupled receptor 128 peptide, thus, represents a candidate allo-peptide that is specifically recognized by 2.102 T cells bound to I-Ep and was identified using bioinformatics. These studies highlight the specific involvement of self-peptides in alloreactivity.