The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/12/1911/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 11, December 1, 1997 1911-1922

Articles

T Cell Receptor (TCR)-induced Death of Immature CD4+CD8+ Thymocytes by Two Distinct Mechanisms Differing in Their Requirement for CD28 Costimulation: Implications for Negative Selection in the Thymus

Jennifer A. Punt*, Wendy Havran§, Ryo Abe{ddagger}, Apurva Sarin*, and Alfred Singer*

From the * Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892; {ddagger} Immune Cell Biology Department, Naval Medical Research Institute, Bethesda, Maryland 20889-5607; and § Department of Immunology, Scripps Research Institute, La Jolla, California 92037

Negative selection is the process by which the developing lymphocyte receptor repertoire rids itself of autoreactive specificities. One mechanism of negative selection in developing T cells is the induction of apoptosis in immature CD4+CD8+ (DP) thymocytes, referred to as clonal deletion. Clonal deletion is necessarily T cell receptor (TCR) specific, but TCR signals alone are not lethal to purified DP thymocytes. Here, we identify two distinct mechanisms by which TCR-specific death of DP thymocytes can be induced. One mechanism requires simultaneous TCR and costimulatory signals initiated by CD28. The other mechanism is initiated by TCR signals in the absence of simultaneous costimulatory signals and is mediated by subsequent interaction with antigen-presenting cells. We propose that these mechanisms represent two distinct clonal deletion strategies that are differentially implemented during development depending on whether immature thymocytes encounter antigen in the thymic cortex or thymic medulla.

Address correspondence to Alfred Singer, Experimental Immunology Branch, NCI/NIH, Bldg 10, Rm 4B-17, Bethesda, MD 20892. Phone: 301-496-5461; Fax: 301-496-0887; E-mail: singera{at}nih.gov Dr. Punt's current address is Haverford College, Haverford, Pennsylvania, 19041. Dr. Abe's current address is Research Institute for Biological Sciences, Science University of Tokyo, 2669 Yamazaki, Noda City, Chiba 278, Japan.

This report was supported in part by National Medical Research and Development Command EQ.0095.003.1412. The views expressed in the article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government.

1 Abbreviations used in this paper: CMJ, cortico medullary junction; DP, double positive; EtBr, ethidium bromide; fasL, fas ligand; FcR, Fc receptor; SP, single positive; TNFR, TNF receptor.


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