A Critical Role for the Innate Immune Signaling Molecule IRAK-4 in T Cell Activation

Suzuki, Nobutaka; Suzuki, Shinobu; Millar, Douglas G.; Unno, Midori; Hara, Hiromitsu; Calzascia, Thomas; Yamasaki, Satoshi; Yokosuka, Tadashi; Chen, Nien Jung; Elford, Alisha R.; Suzuki, Jun; Takeuchi, Akihito; Mirtsos, Christine; Bouchard, Denis; Ohashi, Pamela S.; Yeh, Wen Chen; Saito, Takashi

doi:10.1126/science.1124256

Cited by 103 publications

(88 citation statements)

References 16 publications

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“…These gene-deficient mice, however, do not allow discrimination of kinase versus nonkinase functions. IRAK4 KD knock-in mice have revealed an essential role for IRAK4 kinase activity in pDC IFN-a and macrophage responses to IL-1b and TLR7 (19,20,37), whereas its role in T cell responses is unclear because of conflicting data (20,(38)(39)(40). Because IRAK1 KD knock-in mice have not been reported, the kinase-specific role of IRAK1 in various signaling pathways is unresolved.…”

Section: Discussionmentioning

confidence: 99%

Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell Types

Chiang¹,

Yu²,

Grogan³

2011

The Journal of Immunology

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IL-1R–associated kinases (IRAKs) are important mediators of MyD88-dependent signaling by the TLR/IL-1R superfamily and facilitate inflammatory responses. IRAK4 and IRAK1 function as active kinases and as scaffolds for protein–protein interactions. We report that although IRAK1/4 kinase activity is essential for human plasmacytoid dendritic cell (pDC) activation, it is dispensable in B, T, dendritic, and monocytic cells, which is in contrast with an essential active kinase role in comparable mouse cell types. An IRAK1/4 kinase inhibitor abrogated TLR7/9-induced IFN-α responses in both mouse and human pDCs, but other human immune cell populations activated via TLR7/9 or IL-1R were refractory to IRAK4 kinase inhibition. Gene ablation experiments using small interfering RNA demonstrated an essential scaffolding role for IRAK1 and IRAK4 in MyD88-dependent signaling. Finally, we demonstrate that autoimmune patient (systemic lupus erythematosus and rheumatoid arthritis) serum activates both pDC and B cells, but IRAK1/4 kinase inhibition affects only the pDC response, underscoring the differential IRAK1/4 functional requirements in human immune cells. These data reveal important species differences and elaborate cell type requirements for IRAK1/4 kinase activity.

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Section: Discussionmentioning

confidence: 99%

Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell Types

Chiang¹,

Yu²,

Grogan³

2011

The Journal of Immunology

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“…TLR9-mediated CD4 ϩ T cell activation has been shown to be MyD88 dependent (25). Recently, IL-4 receptor associated kinase, the most proximal downstream signaling molecule after MyD88, has been shown to be essential in eliciting CD4 ϩ T cell activation (26). Finally, TLRs modulate Treg proliferation and their ability to suppress T cell activation (27)(28)(29).…”

Section: Nflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease

Fukata¹,

Breglio²,

Chen³

et al. 2008

The Journal of Immunology

123

110

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Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4+CD45Rbhigh T cells and/or CD4+CD45RblowCD25+ regulatory T cells were isolated and adoptively transferred to RAG1−/− mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [3H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4+CD45Rbhigh T cells expressed TLR2, TLR4, TLR9, and TLR3, and TLR ligands could act as costimulatory molecules. MyD88−/− CD4+ T cells showed decreased proliferation compared with WT CD4+ T cells both in vivo and in vitro. CD4+CD45Rbhigh T cells from MyD88−/− mice did not induce wasting disease when transferred into RAG1−/− recipients. Lamina propria CD4+ T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88−/− cells than mice receiving WT cells. In vitro, MyD88−/− T cells were blunted in their ability to secrete IL-17 but not IFN-γ. Absence of MyD88 in CD4+CD45Rbhigh cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of inflammatory bowel disease.

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“…Interestingly, CD4 or CD8 T cells lacking MyD88 exhibit reduced expansion and impaired survival in vivo (4)(5)(6)(7)(8)(9)(10). IRAK4 has been reported to be recruited to T cell lipid rafts, where it associates with ZAP70 and participates in protein kinase C activation (18). T cells from patients with IRAK4 or MyD88 deficiency exhibit defects in activation and proliferation, highlighting a critical role for IRAK4 signaling in T cell activation and survival (19,20).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

Li¹,

Younger²,

Gartenhaus³

et al. 2015

J. Clin. Invest.

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A Critical Role for the Innate Immune Signaling Molecule IRAK-4 in T Cell Activation

Cited by 103 publications

References 16 publications

Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell Types

Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell Types

The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

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