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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.

Original publication

DOI

10.1172/JCI20569

Type

Journal article

Journal

J Clin Invest

Publication Date

06/2004

Volume

113

Pages

1754 - 1762

Keywords

Animals, DEAD-box RNA Helicases, Epitopes, T-Lymphocyte, Female, Homeodomain Proteins, Ligands, Lymphocyte Activation, Male, Mice, Mice, Inbred CBA, Mice, Transgenic, Minor Histocompatibility Antigens, Peptides, Phenotype, Proteins, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Transplantation Tolerance