T-cell hybridomas and thymocytes undergo programmed cell death (apoptosis) when stimulated with reagents that are normally mitogenic. They also die when stimulated with glucocorticoids such as dexamethasone (Dex). Interestingly, the combination of cellular activation and Dex results in cell survival. The mechanism of this mutual antagonism may be at the level of nuclear transcription factors. Dex treatment prevents the induction of AP-1 (a Jun-Jun or Jun-Fos dimer). Conversely, T-cell receptor (TCR)-mediated activation prevents gene transcription enhanced by a newly described composite glucocorticoid response element. This may represent a novel mechanism for receptor """"""""cross-talk"""""""" in intact cells. It also provides the basis for a new model that deals with thymic selection by proposing a balance between TCR-mediated programmed cell death (negative selection) and its antagonism by corticosteroids (positive selection). Other experiments have explored the function of the CD45 tyrosine phosphatase. CD45 has been shown to be physically associated with the TCR. This association has now been mapped to the delta and zeta chains, the later being of particular interest because it itself is tyrosine phosphorylated after activation. Analysis of CD45 variants that express varying levels of this molecule demonstrated a direct inverse correlation between CD45 levels and spontaneous phosphorylation of zeta. There was also an excellent direct correlation between CD45 levels and TCR-mediated phosphoinositide hydrolysis and Ca2+ flux. Surprisingly, even in the absence of CD45 there were TCR-induced late Ca2+ oscillations. Thus, some but not all components of TCR coupling to Ca2+ regulation is CD45 (tyrosine phosphatase) dependent.
