Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii Academic Article uri icon

abstract

  • Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor-alpha, Toll-like receptor, and G protein-coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-gamma production. Accordingly, Tpl2(-/-) mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-gamma production. Furthermore, reconstitution of Rag2(-/-) mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-gamma defect seen in the Tpl2-deficient mice, confirming a T cell-intrinsic defect. CD4(+) T cells isolated from Tpl2(-/-) mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.

authors

  • Watford, Wendy T
  • Hissong, Bruce D
  • Durant, Lydia R
  • Yamane, Hidehiro
  • Muul, Linda M
  • Kanno, Yuka
  • Tato, Cristina M
  • Ramos, Haydeé L
  • Berger, Alan E
  • Mielke, Lisa
  • Pesu, Marko
  • Solomon, Benjamin
  • Frucht, David M
  • Paul, William E
  • Sher, Alan
  • Jankovic, Dragana
  • Tsichlis, Philip N
  • O'Shea, John J

publication date

  • November 24, 2008