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Epitope Mapping of the Indirect T Cell Response to Allogeneic Class I MHC: Sequences Shared by Donor and Recipient MHC May Prime T Cells That Provide Help for Alloantibody Production¹

Department of Surgery, University of Cambridge, Cambridge, United Kingdom

Indirect allorecognition occurs when T cells recognize donor MHC presented as peptide epitopes by recipient APC, but the precise nature of the epitopes involved remains unclear. Rejection of rat MHC class I-disparate PVG.R8 (RT1.A^a) grafts by PVG.RT1^u (RT1.A^u) recipients is mediated by indirectly restricted CD4 T cells that provide help for the generation of alloantibody. In this study, epitope mapping was performed using a functionally relevant readout (alloantibody production) to identify key peptides that prime an indirect alloimmune response, leading to graft rejection. PVG.RT1^u rats were immunized with a series of overlapping 15-mer peptides (peptides 1–18) that spanned the 1 and 2 domains of the RT1.A^a molecule. Several peptides were able to accelerate both the alloantibody response to the intact RT1.A^a Ag and PVG.R8 heart graft rejection. An immunodominant epitope was identified within the hypervariable region of the 1 domain. Fine mapping of this region with a second series of peptides overlapping by single amino acids confirmed the presence of an eight-amino acid core determinant. Additional "subdominant" epitopes were identified, two of which were located within regions of amino acid homology between the RT1.A^a and RT1.A^u molecules and not, as had been expected, within other hypervariable regions. The contribution of self-epitopes to indirect allorecognition was emphasized by the demonstration that i.v. administration of a 15-mer peptide encompassing one of the subdominant self-determinants diminished the recipient’s ability to mount an alloantibody response on challenge with intact A^a alloantigen. Our findings suggest that cryptic self-epitopes recognized by autoreactive T cells may contribute to allograft rejection and should be considered when designing novel strategies for inducing tolerance to alloantigen.

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