Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii.
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.
Watford
Wendy T
WT
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. watfordw@mail.nih.gov
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
D000818:Animals; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C499308:Rag2 protein, mouse; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C489843:Map3k8 protein, mouse