PKC theta/beta and CYLD Are Antagonistic Partners in the NF kappa B and NFAT Transactivation Pathways in Primary Mouse CD3(+) T Lymphocytes

In T cells PKC theta mediates the activation of critical signals downstream of TCR/CD28 stimulation. We investigated the molecular mechanisms by which PKC theta regulates NF kappa B transactivation by examining PKC theta/beta single and double knockout mice and observed a redundant involvement of PKCh and PKC beta in this signaling pathway. Mechanistically, we define a PKC theta-CYLD protein complex and an interaction between the positive PKC theta/beta and the negative CYLD signaling pathways that both converge at the level of TAK1/IKK/I-kB alpha/NF kappa B and NFAT transactivation. In Jurkat leukemic T cells, CYLD is endoproteolytically processed in the initial minutes of stimulation by the paracaspase MALT1 in a PKC-dependent fashion, which is required for robust IL-2 transcription. However, in primary T cells, CYLD processing occurs with different kinetics and an altered dependence on PKC. The formation of a direct PKC theta/CYLD complex appears to regulate the short-term spatial distribution of CYLD, subsequently affecting NF kappa B and NFAT repressional activity of CYLD prior to its MALT1dependent inactivation. Taken together, our study establishes CYLD as a new and critical PKC theta interactor in T cells and reveals that antagonistic PKC theta/beta-CYLD crosstalk is crucial for the adjustment of immune thresholds in primary mouse CD3(+) T cells.