Protein Kinase Cε Regulates Proliferation and Cell Sensitivity to TGF-1β of CD4+ T Lymphocytes: Implications for Hashimoto Thyroiditis

We have studied the functional role of protein kinase C epsilon (PKC epsilon) in the control of human CD4(+) T cell proliferation and in their response to TGF-1 beta. We demonstrate that PKC epsilon sustains CD4(+) T cell proliferation triggered in vitro by CD3 stimulation. Transient knockdown of PKC epsilon expression decreases IL-2R chain transcription, and consequently cell surface expression levels of CD25. PKC epsilon silencing in CD4 T cells potentiates the inhibitory effects of TGF-1 beta, whereas in contrast, the forced expression of PKC epsilon virtually abrogates the inhibitory effects of TGF-1 beta. Being that PKC epsilon is therefore implicated in the response of CD4 T cells to both CD3-mediated proliferative stimuli and TGF-1 beta antiproliferative signals, we studied it in Hashimoto thyroiditis (HT), a pathology characterized by abnormal lymphocyte proliferation and activation. When we analyzed CD4 T cells from HT patients, we found a significant increase of PKC epsilon expression, accounting for their enhanced survival, proliferation, and decreased sensitivity to TGF-1 beta. The increased expression of PKC epsilon in CD4(+) T cells of HT patients, which is described for the first time, to our knowledge, in this article, viewed in the perspective of the physiological role of PKC epsilon in normal Th lymphocytes, adds knowledge to the molecular pathophysiology of HT and creates potentially new pharmacological targets for the therapy of this disease. The Journal of Immunology, 2011, 187: 4721-4732.