Regulation of mature T lymphocyte proliferation and differentiation by Par-4

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Abstract
The genetic inactivation of the atypical protein kinase C (aPKC) inhibitor, Par‐4, gives rise to increased NF‐κB 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‐κB 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.