Regulation of mature T lymphocyte proliferation and differentiation by Par-4 |
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Authors: | Lafuente María José Martin Pilar Garcia-Cao Isabel Diaz-Meco María Teresa Serrano Manuel Moscat Jorge |
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Institution: | Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Canto Blanco, 28049 Madrid, Spain. |
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Abstract: | The genetic inactivation of the atypical protein kinase C (aPKC) inhibitor, Par-4, gives rise to increased NF-kappaB activation and decreased stimulation of JNK in embryo fibroblasts. Here we have characterized the immunological phenotype of the Par-4(-/-) mice and found that the loss of this gene leads to an increased proliferative response of peripheral T cells when challenged through the TCR. This is accompanied by a higher increase in cell cycle entry and inhibition of apoptosis, with enhanced IL-2 secretion but normal CD25 synthesis. Interestingly, the TCR-triggered activation of NF-kappaB was augmented and that of JNK was severely abrogated. Consistent with previous data from knock outs of different JNKs, NFATc1 activation and IL-4 secretion were augmented in the Par-4-deficient CD4+ T cells, suggesting that the loss of Par-4 drives T-cell differentiation towards a Th2 response. This is compelling evidence that Par-4 is a novel modulator of the immune response through its ability to impact aPKC activity, which translates into lower JNK signaling. |
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