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.

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

“…Negative feedback regulation between Th subsets may explain this phenotype, whereby decreased Th1 differentiation in absence of TPL-2 results in increased Th2 polarization. It has been suggested that defective TCR-mediated activation of ERK in Tpl2 −/− CD4 + T cells results in reduced T-bet and Stat4 expression, and consequently in reduced Th1 differentiation [77]. However, the reduction in TCRinduced ERK phosphorylation in TPL-2-deficient cells is relatively modest and it is possible that TPL-2 has other signaling functions in Th1 differentiation.…”

“…In vitro experiments suggest that IgE switching of purified splenic B cells induced by CD40 plus IL-4 requires TPL-2 activation of ERK [35]. However, IgE antibody production is not defective in Tpl2 −/− mice, possibly due to enhanced Th2 cell differentiation (see above), increasing the available concentration of IL-4, which promotes switching to IgE [77]. Analysis of B cells purified from TPL-2-deficient Nfκb1 −/− mice has also suggested that TLR4 utilizes TPL-2 to activate ERK in B cells [82].…”

“…Surprisingly, transfer experiments with purified T cells suggest that this is due to a T-cell intrinsic defect, rather than an altered innate immune response [77]. Resistance to T. gondii critically depends on IFN-γ production [78], and in vitro experiments revealed that TPL-2 is required for optimal differentiation of naïve T cells to Th1 effector cells producing IFN-γ [77].…”

“…Resistance to T. gondii critically depends on IFN-γ production [78], and in vitro experiments revealed that TPL-2 is required for optimal differentiation of naïve T cells to Th1 effector cells producing IFN-γ [77]. Interestingly, in an ovalbumin-induced model of asthma that is driven by Th2 effector cells, lung inflammation is exacerbated in Tpl2 −/− mice compared to wild-type controls [77]. Negative feedback regulation between Th subsets may explain this phenotype, whereby decreased Th1 differentiation in absence of TPL-2 results in increased Th2 polarization.…”

TPL2 kinase is a suppressor of lung carcinogenesis

“…As a result, TPL2 ablation in mice ameliorates the severity of a variety of inflammatory pathologies (1,6), suggesting that it could be explored as a therapeutic target. In contrast, however, TPL2-deficient mice show increased susceptibility to infection with the T helper 1 (Th1)-inducing parasite T. gondii (7) and ovalbumin-induced bronchoalveolar inflammation (8) because of a T-cell intrinsic defect rather than an altered innate immune response, highlighting cell type-and stimulus-dependent roles for TPL2 in the immune system.…”