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Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii.

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.

SUBMITTER: Watford WT

PROVIDER: S-EPMC2585846 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii.

Watford Wendy T WT Hissong Bruce D BD Durant Lydia R LR Yamane Hidehiro H Muul Linda M LM Kanno Yuka Y Tato Cristina M CM Ramos Haydeé L HL Berger Alan E AE Mielke Lisa L Pesu Marko M Solomon Benjamin B Frucht David M DM Paul William E WE Sher Alan A Jankovic Dragana D Tsichlis Philip N PN O'Shea John J JJ

The Journal of experimental medicine 20081110 12

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- ...[more]

PMID: 19001140

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Project description:Toxoplasma gondii evades host immunity to establish a chronic infection. Here, we assessed the role of parasitophorous vacuole (PV) membrane (PVM)- and intravacuolar network (IVN) membrane-localized dense granule (GRA) proteins in the development of acute and chronic Toxoplasma infection. Deletion of PVM-associated GRA3, GRA7, GRA8, and GRA14 or IVN membrane-associated GRA2, GRA9, and GRA12 in the low-virulence type II Prugniaud (Pru) strain induced severe defects in the development of chronic-stage cysts in vivo without affecting the parasite growth rate or the ability to differentiate into cysts in vitro Acute virulence of the Pru?gra2, Pru?gra3, and Pru?gra4 mutants was reduced but not abolished. In contrast, the Pru?gra12 mutant was avirulent in mice and Pru?gra12 parasites failed to establish a chronic infection. High-virulence type I strain RH?gra12 parasites also exhibited a major defect in acute virulence. In gamma interferon (IFN-?)-activated macrophages, type I RH?gra12 and type II Pru?gra12 parasites resisted the coating of the PVM with host immunity-related GTPases as effectively as the parental type I RH?ku80 and type II Pru?ku80 strains, respectively. Despite this resistance, ?gra12 PVs ultimately succumbed to IFN-?-activated host cell innate immunity. Our findings uncover a key role for GRA12 in mediating resistance to host IFN-? and reveal that many other IVN membrane-associated GRA proteins, as well as PVM-localized GRA proteins, play important roles in establishing chronic infection.IMPORTANCE Toxoplasma gondii cysts reactivate during immune deficiency and cause fatal encephalitis. Parasite molecules that coordinate the development of acute and chronic infection are poorly characterized. Here, we show that many intravacuolar network membrane and parasitophorous vacuole membrane-associated dense granule (GRA) proteins orchestrate the development of chronic cysts in vivo A subset of these GRA proteins also modulate acute virulence, and one protein that associates with the intravacuolar network membranes, namely GRA12, was identified as a major virulence factor required for parasite resistance to host gamma interferon (IFN-?). Our results revealed that many parasitophorous vacuole membrane and intravacuolar network membrane-associated GRA proteins are essential for successful chronic infection.

Dataset Information

Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii.

Publications

Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii.

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