A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor-Ligand Complex

doi:10.1084/jem.189.10.1531

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J. Exp. Med., Volume 189, Number 10, May 17, 1999 1531-1544

A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor-Ligand Complex

By Calvin B. Williams,^* Deborah L. Engle, Gilbert J. Kersh, J. Michael White, and Paul M. Allen

From the ^* Department of Pediatrics and the Department of Pathology, Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and thedevelopment of major histocompatibility complex class II- restrictedT cells. Our studies use the 3.L2 T cell receptor (TCR) transgenicmouse, in which T cells are specific for Hb(64-76)/I-E^k and positively selected on I-E^k plus self-peptides. To this endogenous peptide repertoire, wehave individually added one of six well-characterized 3.L2 ligands.This transgenic approach expands rather than constrains the repertoireof self-peptides. We find that a broad range of ligands producenegative selection of thymocytes in vivo. When compared with thein vitro TCR-ligand binding kinetics, we find that these negativelyselecting ligands all have a half-life of 2 s or greater. Additionally,one of two ligands examined with no detectable binding to the3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhancesthe positive selection of transgenic thymocytes in vivo. Together,these data establish a kinetic threshold between negative andpositive selection based on the longevity of TCR-ligandcomplexes.

Key words: T cell receptor; thymocyte; transgenic; selection; altered peptide ligand

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