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- Title
Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii.
- 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
- 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.
- Publication
The Journal of experimental medicine, 2008, Vol 205, Issue 12, p2803
- ISSN
1540-9538
- Publication type
Journal Article
- DOI
10.1084/jem.20081461