Abstract
Abstract Previously, we showed that PKCθ signaling is neutralized in human T cells when anti-pPKCθ (against Thr538 phosphorylation) is delivered intracellularly, using a cell-penetrating peptide mimic (PTDM). Using a humanized model of graft-vs-host disease, we further demonstrated these effects were durable and provided a survival benefit when anti-pPKCθ-treated human PBMCs were used to induce disease. Of note, intracellular delivery of anti-pPKCθ altered PKCθ cellular localization compared to mock-treated cells. In the present study, we show that PKCθ localization is modulated in TH1, TH2, TH17, and iTregs following anti-pPKCθ delivery, and this modulation influences TH cell fate in vitro. It has been reported that PKCθ stimulates STAT3 transcription via the NF-κB pathway and has differential effects on STAT4 and STAT6. We found that, through its cellular localization, pPKCθ may differentially regulate the expression and translocation of STAT proteins, as well as master transcription factors, to ultimately control T cell differentiation programs. Altogether, we demonstrate that we can change the subcellular localization of PKCθ using a cell-penetrating antibody and as a result, can redirect the differentiation potential of T helper cells.
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