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

作者：Watford Wendy T; Wang Chun Chi; Tsatsanis Christos; Mielke Lisa A; Eliopoulos Aristides G; Daskalakis Constantine; Charles Nicolas; Odom Sandra; Rivera Juan; O'Shea John; Tsichlis Philip N^*

来源：The Journal of Immunology, 2010, 184(1): 105-113.

DOI：10.4049/jimmunol.0803730

The protein kinase encoded by the Tpl2 proto-oncogene regulates ERK activation and cytokine gene expression in macrophages in response to LPS and TNF-alpha. 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 wildtype 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(-/-) Thl 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 Thl and Th2 cells depends on positive feedback signals from the T cells, themselves, the functional defect of the Tpl2(-/-) Thl cells provides a mechanistic explanation for the T cell autonomous Th2 polarization in Tpl2(-/-) mice. The Journal of Immunology, 2010, 184: 105-113.

• 出版日期2010-1-1