Intragraft selection of the T cell receptor repertoire by class I MHC sequences in tolerant recipients.

Abstract

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 [alpha(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 Vbeta spectrotyping of the splenocytes and cardiac allografts showed that the Vbeta 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 Vbeta7, Vbeta11, Vbeta13, Vbeta 14, and Vbeta15 genes. Moreover, we found a positive correlation between the alteration of Vbeta 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 Vbeta genes.