Inhibition of Human T Cell Activation by Novel Src Kinase Inhibitors Is Dependent upon the Complexity of the Signal Delivered to the Cell

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Abstract
The activity of a novel series of protein tyrosine kinase inhibitors that are selective for the Src family has been assessed. The activity of these compounds [named CT-SKI (Celltech Src kinase inhibitors)] was investigated by assessing their potential to modulate T cell receptor activation, an event thought to involve the Src kinases Lck and Fyn. This series of compounds contained low-nanomolar inhibitors of Src kinases with selectivity over Csk, epidermal growth factor receptor kinase, protein kinase C, and ζ-associated 70-kDa protein. These compounds were shown to attenuate anti-CD3-induced T cell proliferation and block interleukin (IL)-2, IL-4, and interferon-γ production, and CD25 expression in anti-CD3-activated T cells. In addition, inhibition of anti-CD3-induced, but not phorbol ester and calcium ionophore-induced IL-2 production, correlated with inhibition of in vitro Lck kinase activity. When more complex stimuli were used to activate T cells, as in the mixed lymphocyte reaction (MLR), these inhibitors proved to be less effective and inhibition of the MLR did not correlate with inhibition of isolated Lck enzyme. Interestingly, inhibition of anti-CD3-induced proliferation could be reversed by the addition of exogenous IL-2, indicating that signaling through the IL-2 receptor may not be critically dependent on any functional Src enzymes.