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Involvement of Classical and Novel Protein Kinase C Isoforms in the Response of Human V9V2 T Cells to Phosphate Antigens¹

Barbara Cipriani^*,, Heather Knowles^*, Lanfen Chen^*, Luca Battistini and Celia F. Brosnan^2,*,

Departments of ^* Pathology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and Istituto di Ricovero e Cura a Carattere Scientifico, Fondazione Santa Lucia, Rome, Italy

Human T cells expressing the V9V2 gene segments are activated polyclonally by phosphoantigens found on a wide variety of pathogenic organisms. After ligand exposure, V9V2 T cells proliferate and rapidly secrete large amounts of cytokines and chemokines that contribute to the innate immune response to these pathogens. Neither APCs nor costimulatory molecules are required. In this study we examined whether these phosphoantigens activate protein kinase C (PKC). This novel PKC isoform is essential for Ag signaling through the TCR in a costimulation-dependent fashion. The results showed that isopentenyl pyrophosphate (IPP), a soluble phospholigand released by mycobacteria, led to the rapid and persistent activation of PKC in T cells, as determined by evidence of translocation and phosphorylation. In contrast, no ligand-dependent response was detected for PKC/ or PKC. Using the inhibitors Gö6976 and rottlerin, a role for both conventional and novel PKC isoforms in IPP-induced proliferation, CD25 expression, and cytokine and chemokine production was demonstrated. Gel-shift assays indicated that the transcription factors NF-B and AP-1 were downstream targets of PKC activation. IPP also induced the rapid and persistent phosphorylation of extracellular signal-regulated kinases 1 and 2, p38 mitogen-activated kinase, and stress-activated kinase/c-Jun N-terminal kinase, but only an inhibitor of conventional PKCs blocked these responses. We conclude that the T cell response to phosphoantigens is regulated by both novel and conventional PKC isoforms, with PKC being more responsive to ligand stimulation and PKC/ to growth-factor availability.

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