Ablation of Tumor Progression Locus 2 Promotes a Type 2 Th Cell Response in Ovalbumin-Immunized Mice

Abstract

The protein kinase encoded by the Tpl2 proto-oncogene regulates ERK activation and cytokine gene expression in macrophages in response to LPS and TNF-α. In this study we show that OVA-immunized Tpl2−/− mice express high levels of IgE and develop more severe bronchoalveolar eosinophilic inflammation than Tpl2+/+ controls, when challenged with OVA intranasally. Bronchoalveolar exudates and supernatants of OVA-stimulated splenocytes from immunized Tpl2−/− mice express elevated levels of IL-4 and IL-5, suggesting that Tpl2 ablation promotes the Th2 polarization of the T cell response. Anti-CD3 stimulation of CD4+ T cells of wild-type and Tpl2 knockout mice revealed that Tpl2 ablation gives rise to a cell autonomous T cell defect that is primarily responsible for the Th2 polarization of the T cell response to Ag. This observation was further supported by experiments addressing the expression of Th1 and Th2 cytokines in OVA-stimulated mixed cultures of CD4+ T cells from Tpl2+/+/OT2 or Tpl2−/−/OT2 mice and dendritic cells from Tpl2+/+ or Tpl2−/− mice. Further studies revealed that Th1 cells express significantly higher levels of Tpl2 than Th2 cells. As a result, Tpl2−/− Th1 cells exhibit a stronger defect in ERK activation by anti-CD3 than Th2 cells and express low levels of T-bet. Given that the development of Th1 and Th2 cells depends on positive feedback signals from the T cells, themselves, the functional defect of the Tpl2−/− Th1 cells provides a mechanistic explanation for the T cell autonomous Th2 polarization in Tpl2−/− mice.