Pediatric Rheumatology Online Journal → August 2003 →  Basic Immunology  → Abstract #170   

AN ENDOGENOUSLY EXPRESSED T CELL RECEPTOR ANTAGONIST INHIBITS T CELL PROLIFERATION AND THE FORMATION OF T CELL MEMORY

C. B. Williams,¹ D. Haribhai,¹ M. M. Meyer.²

¹Pediatrics, Medical College of Wisconsin, Milwaukee, WI; ²Pediatrics, Washington University School of Medicine, St. Louis, MO

T cell receptor antagonists are peptide/MHC ligands that inhibit antigen-specific T cell proliferation. The general mechanisms by which peptide antagonists block T cell responses may have important therapeutic implications. We have investigated the mechanism of T cell receptor antagonism in vivo using a novel murine transgenic system based on an allelic variant of the self-antigen hemoglobin. In this model antigen system, the general T cell response is directed against amino acids 64-76 of the hemoglobin beta chain and is restricted by the MHC class II molecule I-E^k (Hbb^d(64-76)/I-E^k). The T cell clone 3.L2 is representative of all Hb(64-76) reactive T cells in that the primary T cell receptor contact residue in the Hb(64-76) peptide is asparagine at position 72. When this amino acid is replaced by isoleucine, the resulting I72 peptide acts as a T cell receptor antagonist for 3.L2 T cells by inhibiting activation and IL-2 production in vitro. Here, we examine the ability of the antagonist I72 to inhibit 3.L2 T cell proliferation in vivo by adoptively transferring transgenic 3.L2 T cells into mice expressing I72/I-E^k complexes on all antigen-presenting cells. Immunization of transfer recipients with Hb(64-76) peptide reveals a dramatically reduced primary 3.L2 T cell response. This inhibition cannot be overcome by increasing the dose of the immunizing peptide. Secondary B cell follicle formation is delayed and T cell memory is abrogated in I72 mice relative to littermate controls. 3.L2 T cells accumulate in and are eliminated from the spleens of I72 mice, reflecting an important in vivo component of the mechanism of T cell receptor antagonism.