Positive feedback regulation of PLCγ1/Ca2+ signaling by PKCθ in restimulated T cells via a Tec kinase‐dependent pathway

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Abstract
PKCθ plays an essential role in activation of mature T cells. Here, we report that the TCR/CD28‐induced tyrosine phosphorylation and activation of PLCγ1 was significantly impaired in PKCθ –/– primary, restimulated T cells. Consistent with this finding, receptor‐induced Ca2+ mobilization, NF‐AT DNA‐binding activity and the membrane translocation of PKCα, a PLCγ1‐dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant‐negative PLCγ1 mutant blocked the PKCθ‐induced activation of an AP‐1 reporter gene in Jurkat and primary cells. Regulation of PLCγ1 signaling by PKCθ required the tyrosine kinase Tec since a dominant‐negative Tec mutant blocked PKCθ‐induced AP‐1 (but not NF‐κB) activation. In addition, wild‐type Tec, but not Itk or Rlk, potently activated AP‐1. Furthermore, Tec was found to constitutively associate with PKCθ, an interaction that like AP‐1 activation required the pleckstrin‐homology domain of Tec. These findings define a novel PKCθ‐initiated pathway that regulates Ca2+ signaling and AP‐1 activation via Tec and PLCγ1. Moreover, they identify Tec as a key point downstream of PKCθ, where TCR‐ and PKCθ‐induced signaling pathways, leading to AP‐1 versus NF‐κB activation, diverge in T cells.