Co-receptor (CD4/CD8) engagement enhances CD3-induced apoptosis in thymocytes: Implications for negative selection

David J. McConkey, Lisa Fosdick, Luciano D'Adamio, Mikael Jondal, Sten Orrenius

Research output: Contribution to journalArticlepeer-review

Abstract

Negative selection of self-reactive immature T cells is mediated by TCR engagement and is thought to occur via apoptosis (programmed cell death). The requirement for the co-receptors CD4 and CD8 in negative selection has been demonstrated, but the biochemical mechanisms underlying their involvement in this process remain undefined. Here we present evidence that co-receptor engagement dramatically enhances CD3-induced endonuclease activation and cell death characteristic of apoptosis in immature thymocytes. The responses are associated with increased tyrosine phosphorylation of a number of cellular substrates, including the γ isoform of phospholipase C, and with increased association of tyrosine phosphoproteins, including the protein tyrosine kinase p56(lck), with the TCR complex. Co-receptor engagement also potentiated CD3-mediated Ca2+ increases via a mechanism dependent upon tyrosine kinase activation. Sustained Ca2+ availability was found to be necessary for endonuclease activation and apoptosis to occur. We suggest that CD4 and CD8 may participate in negative selection by enhancing TCR/CD3- induced tyrosine kinase activation and sustained Ca2+ increases that lead to endonuclease activation and apoptosis in self-reactive CD4+CD8+ thymocytes.

Original languageEnglish (US)
Pages (from-to)2436-2443
Number of pages8
JournalJournal of Immunology
Volume153
Issue number6
StatePublished - Sep 15 1994
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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