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J. Exp. Med.,
Volume 186, Number 11, December 1, 1997 1911-1922
By
From the * Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892; 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.
Immune Cell Biology Department, Naval Medical Research Institute, Bethesda, Maryland 20889-5607;
and § Department of Immunology, Scripps Research Institute, La Jolla, California 92037
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