Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen

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Abstract
EFFECTOR T cells are restricted to recognizing antigens associated with major histocompatibility complex (MHC) molecules1. Specific recognition is mediated by the αβ heterodimer of the T-cell receptor (TCR)/CD3 complex2,3, although other membrane components are involved in T-cell antigen recognition and functions. There has been much controversy in this regard over the part played by the CD4 glycoprotein. It is known that expression of CD4 correlates closely with the cell's ability to recognize antigens bound to class II MHC molecules4,5 and that CD4 can bind to class II molecules6. Also monoclonal antibodies to CD4 can modify signals generated through the TCR/CD3 complex7–10. It has therefore been proposed that CD4 binds to class II molecules, coaggregates with the TCR–CD3 complex and aids the activation of T cells. But given that TCR can itself impart restriction on the cell, it remains unclear whether the contribution of CD4-derived signals to those generated through the TCRaαβ–CD3 complex is central to this activation. Here we report that when preceded by ligation of CD4, signalling through TCRαβ results in T cell unresponsiveness due to the induction of activation dependent cell death by apoptosis. These results imply that CD4 is critically involved in determining the outcome of signals generated through TCR, and could explain why the induction of effector T cells needs to be MHC-restricted.