Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby.
T cell reactivity to minor histocompatibility (mH) antigens is responsible for rejection of HLA-matched allografts, limiting the effectiveness of transplantation for the treatment of end-stage organ failure. The deadbox gene Dby is located on the Y chromosome and encodes an mH antigen that prompts rejection of male tissues by female mice. Establishing a network of regulatory T (T(reg)) cells that is capable of coercing naive cells to adopt a tolerant phenotype offers an attractive strategy for immune intervention in such deleterious immune responses. While various approaches have successfully induced a dominant form of transplantation tolerance, they share the propensity to provoke chronic, incomplete activation of T cells. By identifying the T cell receptor (TCR) contact sites of the dominant epitope of the Dby gene product, we have designed an altered peptide ligand (APL) that delivers incomplete signals to naive T cells from A1 infinity RAG1(-/-) mice that are transgenic for a complementary TCR. Administration of this APL to female transgenic mice polarizes T cells toward a regulatory phenotype, securing a form of dominant tolerance to male skin grafts that is capable of resisting rejection by naive lymphocytes. Our results demonstrate that incomplete signaling through the TCR may establish a network of T(reg) cells that may be harnessed in the service of transplantation tolerance.
Chen
Tse-Ching
TC
University of Oxford, Sir William Dunn School of Pathology, Oxford, United Kingdom.
Waldmann
Herman
H
Fairchild
Paul J
PJ
D000818:Animals; D053487:DEAD-box RNA Helicases; D018984:Epitopes, T-Lymphocyte; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D011506:Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D023001:Transplantation Tolerance / Q000502:physiology*
D018984:Epitopes, T-Lymphocyte; D018398:Homeodomain Proteins; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein; C115600:Ddx3y protein, mouse; D053487:DEAD-box RNA Helicases