Intragraft Selection of the T Cell Receptor Repertoire by Class I MHC Sequences in Tolerant Recipients

Background

Allograft tolerance of ACI (RT1^a) recipients to WF (RT1^u) hearts can be induced by allochimeric class I MHC molecules containing donor-type (RT1A^u) immunogenic epitopes displayed on recipient-type (RT1A^a) sequences. Here, we sought the mechanisms by which allochimeric sequences may affect responding T cells through T cell receptor (TCA) repertoire restriction.

Methodology/Principal Findings

The soluble α_1h ^u]-RT1.A^a allochimeric molecule was delivered into ACI recipients of WF hearts in the presence of sub-therapeutic dose of cyclosporine (CsA). The TCR Vβ spectrotyping of the splenocytes and cardiac allografts showed that the Vβ gene families were differentially expressed within the TCR repertoire in allochimeric- or high-dose CsA-treated tolerant recipients at day +5 and +7 of post-transplantation. However, at day 30 of post-transplantation the allochimeric molecule-treated rats showed the restriction of TCR repertoire with altered dominant size peaks representing preferential clonal expansion of Vβ7, Vβ11, Vβ13, Vβ 14, and Vβ15 genes. Moreover, we found a positive correlation between the alteration of Vβ profile, restriction of TCR repertoire, and the establishment of allograft tolerance.

Conclusions

Our findings indicate that presentation of allochimeric MHC class I sequences that partially mimic donor and recipient epitopes may induce unique tolerant state by selecting alloresponsive Vβ genes.