EGF family members (including AR) are initially expressed as transmembrane proteins and released into the extracellular region after cleavage by metalloproteases, particularly ADAM17 [22] . To determine whether T cells also initially expressed surface AR and then released the soluble cleavage product, surface AR was stained during TCR activation in the presence or absence of the ADAM17/TACE inhibitor TAPI-1 [32] . TAPI-1 increased AR expression on the surface of both CD4 and CD8 T cells measured by frequency ( Figure 3A ) or fluorescence intensity (data not shown). Conversely, TAPI-1 decreased soluble AR in the supernatant ( Figure 3B ). In the absence of TAPI-1, AR expression on T cells gradually decreased and was barely detectable after 24 hours. As ADAM17 mRNA was detected by RT-PCR in resting human T cells and upregulated on activation (data not shown), these results suggested that AR was first synthesized as a membrane protein on human T cells and then released by ADAM17 cleavage, as in other cell types [34, 35] .