Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby
Tse-Ching Chen, … , Herman Waldmann, Paul J. Fairchild
Tse-Ching Chen, … , Herman Waldmann, Paul J. Fairchild
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1754-1762. https://doi.org/10.1172/JCI20569.
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Article Immunology

Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby

Abstract

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 (Treg) 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 ∞ 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 Treg cells that may be harnessed in the service of transplantation tolerance.

Authors

Tse-Ching Chen, Herman Waldmann, Paul J. Fairchild

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Figure 1

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Identification of the H-2Ek binding motif of the dominant epitope of Dby...
Identification of the H-2Ek binding motif of the dominant epitope of Dby. (A) Proliferative responses of naive female A1 ∞ RAG1–/– T cells to the 479–493 peptide from the male antigen, Dby (filled circles), compared with its female homolog, Dbx (open triangles). (B) Competition binding assay showing the enhanced capacity of Dby (filled circles) to compete with HEL1-18 for binding to H-2Ek compared to Dbx (open triangles), as determined by the extent of inhibition of IL-2 secretion by the 2G7.1 hybridoma. (C) Stimulatory capacity of analogs of the Dby epitope, substituted with alanine at putative TCR contact residues. (D) Schematic diagram highlighting residues of the Dby epitope that determine its interaction with H-2Ek and the A1 TCR. The conventional arrows define those residues that interact directly with either the MHC or TCR, while the broad arrow denotes the putative primary TCR contact residue. All data shown are representative of at least three independent experiments.