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.


RESULTS
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.
Liu
Dahai
D
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, Los Angeles, CA, USA.
Shen
Xiu-Da
XD
Zhai
Yuan
Y
Lam
Wengsi
W
Liao
Jingying
J
Busuttil
Ronald W
RW
Ghobrial
Rafik M
RM
D000465:Algorithms; D000818:Animals; D017690:Cell Transplantation / Q000379:methods*; D000939:Epitopes / Q000737:chemistry; D005805:Genes, MHC Class I; D007108:Immune Tolerance; D054992:Immunological Synapses; D008297:Male; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D051381:Rats; D017208:Rats, Wistar; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000939:Epitopes; D011948:Receptors, Antigen, T-Cell