Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine 
kinases (SFK), including p56(Lck) (Lck). Given the central importance of Lck in 
transmitting signals from the T-cell receptor (TCR) signaling complex and the 
potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent 
could provide a novel route of immunomodulation via targeted inhibition of 
antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated 
signal transduction, cellular proliferation, cytokine production, and in vivo 
T-cell responses. However, dasatinib-mediated inhibition does not induce 
apoptosis because the effect is reversible or may be overcome by signals 
bypassing the TCR, such as phorbol ester. Signal transduction and proliferative 
responses via IL-2 remain essentially unperturbed, suggesting that dasatinib 
displays specificity for TCR signaling. In addition, dasatinib combined with 
cyclosporine A or rapamycin led to a much more potent inhibition of T-cell 
activation, suggesting that targeted inhibition of Lck could be a useful adjunct 
for enhanced immunomodulation. In combination with currently available 
immunomodulatory agents, SFK inhibition could potentially increase 
immunomodulatory efficacy while minimizing toxicity of individual agents.