Differential regulation of accessory mitogenic signaling receptors by the T cell antigen receptor

In addition to the antigen receptor, resting T cells express a number of receptors that can be stimulated to generate proliferative signals. These "accessory" receptors require co-expression of the T cell receptor (TCR), suggesting that they channel their signals via secondary activation of the signal transduction function of the CD3-TCR complex. Little is known about how different receptors control each other's function when one or more stimuli are presented at the same time. In order to study the regulation of accessory receptors by the CD3-TCR and vice versa, we have investigated the activation of the CD2 cell adhesion molecule receptor and the pertussis toxin receptor, a 43 kDa plasma membrane protein. Both receptors can activate signal transduction pathways in T cells similar to that of the CD3-TCR, including increases in Ca2+ and phosphatidylinositol turnover. They are also similar in that they utilize the antigen receptor to transmit their signals to the cell since CD3-TCR(-) mutants cannot be activated via either CD2 or the toxin receptor. We have previously shown that submaximal stimulation of the CD3-TCR blocks second messenger generation and proliferation in response to pertussis toxin. This heterologous desensitization was unidirectional since activation of the toxin receptor had no effect on CD3-TCR function. Here we extend these studies to show that activation of both CD2 and the toxin receptor led to rapid tyrosine phosphorylation of three similar proteins. Submaximal stimulation of the CD3-TCR completely inhibited toxin receptor-stimulated tyrosine protein kinase activity but did not desensitize CD2 function as determined by activation of tyrosine protein phosphorylation. Furthermore, CD2 stimulation did not lead to desensitization of the pertussis toxin receptor. These data support a system of complex regulatory relationships between different signaling receptors and suggest a model for signal integration and inter-receptor cross-talk in T cell activation.