Resting lymphocyte kinase (Rlk/Txk) targets lymphoid adaptor SLP-76 in thecooperative activation of interleukin-2 transcription in T-cells

Blk/Txk is a T-cell-specific member of the Btk/Tec family of tyrosine kinas es, whereas SLP-76 is a lymphoid adaptor that is essential for pre-TcR and mature TcR signaling, Although Rlk deficient T-cells show partial defects i n T-cell proliferation, Rlk can complement ITK-/- cells with multiple defec ts in TcR initiated early events and interleukin (IL)-2 production. A key q uestion is the nature of the target of Rlk responsible for bridging the TcR with the activation of IL-2 transcription. In this study, we identify a pa thway in which Rlk phosphorylates SLP-76 leading to the phosphorylation of PLC gamma 1, activation of ERKs, and the synergistic up-regulation of TcR-d riven IL-2 NFAT/AP-1 transcription, Rlk phosphorylated the N-terminal regio n of SLP-76, a region that has been previously shown to serve as a target f or ZAP-70. Loss of N-terminal YESP/YEPP sites of SLP-76 or the Rlk kinase a ctivity attenuated cooperativity between Rlk and SLP-76. These observations support a model where the TcR can utilize Rlk (as well as ZAP-70) in the p hosphorylation of key sites in SLP-76 leading to the up-regulation of Th1 p referred cytokine IL-2.