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© The Rockefeller University Press, 0022-1007/1999/1/13/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 1, January 4, 1999 13-24

Articles

A T Cell Receptor–specific Blockade of Positive Selection

Kristin K. Baldwin*, Philip A. Reay§, Lawren Wu*, Andrew Farr{ddagger}, and Mark M. Davis*

From the * Howard Hughes Medical Institute, and the Department of Microbiology and Immunology, Stanford University, Stanford, California 94305; the {ddagger} Department of Biological Structure and Department of Immunology, School of Medicine, University of Washington, Seattle, Washington 98195; and the § Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, OX3 9DU, United Kingdom

To investigate the influence of endogenous peptides on the developmental processes that occur during thymocyte selection, we have used monoclonal antibodies that preferentially recognize the major histocompatibility complex (MHC) molecule I-Ek when it is bound to the moth cytochrome c peptide (88–103). One of these antibodies (G35) specifically blocks the positive selection of transgenic thymocytes expressing a T cell receptor that is reactive to this peptide– MHC complex. Furthermore, G35 does not block the differentiation of transgenic T cells bearing receptors for a different I-Ek–peptide complex. This antibody recognizes a subset of endogenous I-Ek–peptide complexes found on a significant fraction of thymic antigen-presenting cells, including cortical and medullary epithelial cells. The sensitivity of G35 to minor alterations in peptide sequence suggests that the thymic peptide–MHC complexes that mediate the positive selection of a particular class II MHC–restricted thymocyte are structurally related to the complexes that can activate it in the periphery.

Key Words: thymic selection • peptides • CD4+ T cell • thymocyte • monoclonal antibodies

Address correspondence to Mark M. Davis, Beckman Center, Unit in Molecular and Genetic Medicine, Stanford University School of Medicine, Stanford, CA 94305-5428. Phone: 650-723-7962; Fax: 650-498-7771; E-mail: mdavis{at}cmgm.stanford.edu

K.K. Baldwin was a Howard Hughes Predoctoral Fellow. L.C. Wu is presently supported by a fellowship from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation and previously by an Immunology Training Grant. The Howard Hughes Medical Institute provided postdoctoral support for P.A. Reay and support for this project in the laboratory of M.M. Davis. Additional support for A. Farr was provided by NIH grants AI24137 and AG04360.

K. Baldwin's present address is H.H.M.I./Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, 701 West 168th St., New York, NY 10032.

K.K. Baldwin and P.A. Reay contributed equally to the work described in this paper.

Abbreviations used: MCC, moth cytochrome c..


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