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

Journal article

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.

Authors: Chen, T; Waldmann, H; Fairchild, P

• Journal: Journal of clinical investigation
• Volume: 113
• Issue: 12
• Pages: 1754-1762
• Publication date: 2004-06-01
• DOI: 10.1172/jci20569
• EISSN: 1558-8238
• ISSN: 0021-9738
• Language: English
• Keywords: Transplantation Tolerance; Ligands; Male; Female; Phenotype; Mice, Inbred CBA; Receptors, Antigen, T-Cell; Homeodomain Proteins; Mice, Transgenic; Minor Histocompatibility Antigens; Peptides; Epitopes, T-Lymphocyte; Signal Transduction; Lymphocyte Activation; DEAD-box RNA Helicases; Proteins; Animals; T-Lymphocytes; Mice