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Science 14 May 1999:
Vol. 284. no. 5417, pp. 1187 - 1191
DOI: 10.1126/science.284.5417.1187
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Reports

Inactivation of Misselected CD8 T Cells by CD8 Gene Methylation and Cell Death

Gary A. Pestano, 13 Yaling Zhou, 13 Linda A. Trimble, 13 John Daley, 2 Georg F. Weber, 14 Harvey Cantor 13*

Misselected CD8 cells that express T cell receptors (TCRs) that do not recognize class I major histocompatibility complex (MHC) protein can emerge from thymic selection. A postthymic quality control mechanism that purges these cells from the repertoire is defined here. The failure of mature CD8 cells to simultaneously engage their TCR and CD8 coreceptor triggers an activation process that begins with inhibition of CD8 gene expression through remethylation and concludes with up-regulation of surface Fas and Fas ligand and cellular apoptosis. Thus, inhibition of a death signal through continued TCR-CD8 coengagement of MHC molecules is a key checkpoint for the continued survival of correctly selected T cells. Molecular defects that prevent delivery of the death signal to mistakenly selected T cells underlie the expansion of double-negative T cells, which is the cellular signature of a subset of systemic autoimmune diseases.

1 Department of Cancer Immunology and AIDS;
2 Department of Adult Oncology, Dana Farber Cancer Institute;
3 Department of Pathology;
4 Department of Medicine; Harvard Medical School, 44 Binney Street, Boston MA 02115, USA.
*   To whom correspondence should be addressed. E-mail: Harvey_Cantor{at}DFCI.harvard.edu

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