Abstract
BackgroundAllograft tolerance of ACI (RT1a) recipients to WF (RT1u) hearts can be induced by allochimeric class I MHC molecules containing donor-type (RT1Au) immunogenic epitopes displayed on recipient-type (RT1Aa) sequences. Here, we sought the mechanisms by which allochimeric sequences may affect responding T cells through T cell receptor (TCA) repertoire restriction.Methodology/Principal FindingsThe soluble [α1h u]-RT1.Aa 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.ConclusionsOur 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.
Highlights
The possible mechanisms underlying the development of transplantation tolerance include clonal deletion of alloreactive cells, clonal anergy, cell-mediated suppression, and ‘‘infectious’’ tolerance [1]
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 Vb genes
Analysis of T cell responses to nominal protein or transplantation antigens has shown that constraints in antigen processing and presentation usually limit the T cell responses to one or two dominant determinants [3], and that, in humans, T cells responding to dominant allopeptides had limited TCR-Vb gene usage [10,11]
Summary
The possible mechanisms underlying the development of transplantation tolerance include clonal deletion of alloreactive cells, clonal anergy, cell-mediated suppression, and ‘‘infectious’’ tolerance [1]. Studies on the mechanisms responsible for the establishment of transplantation tolerance point to the immune regulation as the major determinant. T cells react to allogeneic MHC molecules by displaying a dominant determinant on donor MHC antigens and are restricted by self-MHC elements [9,10,11]. It was shown previously that the alteration of critical amino acid residues in such immunodominant determinants inhibited T cell proliferative responses, induced T cell anergy and altered host immune responses toward native antigens [12,13,14,15]. Allograft tolerance of ACI (RT1a) recipients to WF (RT1u) hearts can be induced by allochimeric class I MHC molecules containing donor-type (RT1Au) immunogenic epitopes displayed on recipient-type (RT1Aa) sequences. We sought the mechanisms by which allochimeric sequences may affect responding T cells through T cell receptor (TCA) repertoire restriction
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