Anti-TCR-specific DNA vaccination demonstrates a role for a CD8+ T cell clone in the induction of allograft tolerance by donor-specific blood transfusion.
Donor-specific allograft tolerance can be induced in the adult rat by pregraft donor-specific blood transfusion (DST). This tolerance appeared to be mediated by regulatory cells and to the production of the suppressive cytokine TGF-beta1. A potential immunoregulatory CD8+ clone bearing a Vbeta18-Dbeta1-Jbeta2.7 TCR gene rearrangement was previously identified in DST-treated recipients. To assess the functional role of this T cell clone in the induction of tolerance by DST, we have vaccinated DST-treated recipients with a plasmid construct encoding for the Vbeta18-Dbeta1-Jbeta2.7 TCR beta-chain. DST-induced allograft tolerance was abolished by anti-TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination in six of seven recipients, whereas vaccination with the vector alone, or with the construct encoding a TCR Vbeta13 beta-chain, had no effect. However, the transcript number of the Vbeta18-Dbeta1-Jbeta2.7 chain was unchanged in allografts from vaccinated DST-treated rats, suggesting that this clone was not depleted by vaccination, but rather was altered in its function. Moreover, TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination restored the anti-donor alloantibody production, partially restore the capacity of spleen cells from tolerized recipients to proliferate in vitro against donor cells, and decreased the inhibitory effect of TGF-beta1, seen in DST-treated recipients, in spleen cells from vaccinated DST-treated ones. This study strongly suggests that this CD8+ TCR Vbeta18-Dbeta1-Jbeta2.7 T cell clone has an effective immunoregulatory function in allograft tolerance induced by DST.
Vignes
C
C
Institut National de la Santé et de la Recherche Médicale Unité 437 "Immunointervention dans les allo-et xeno-transplantations" and Institut de Transplantation et de Recherche en Transplantation, Nantes, France.
Chiffoleau
E
E
Douillard
P
P
Josien
R
R
Pêche
H
H
Heslan
J M
JM
Usal
C
C
Soulillou
J P
JP
Cuturi
M C
MC
D000818:Animals; D001803:Blood Transfusion; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017637:Clonal Deletion / Q000235:genetics; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D019674:Genes, T-Cell Receptor beta / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D007273:Injections, Intramuscular; D007518:Isoantibodies / Q000096:biosynthesis; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016042:Transplantation, Heterotopic; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D007518:Isoantibodies; D012333:RNA, Messenger; D019444:Vaccines, DNA; D014765:Viral Vaccines