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Article ; Online: Genetic insights into Map3k-dependent proliferative expansion of T cells.

Suddason, Tesha / Gallagher, Ewen

2016 Volume 15, Issue 15, Page(s) 1956–1960

Abstract: Mapks are important regulators of T cell proliferative expansion and cell cycle progression. Detailed genetic analysis of unconventional iNKT cells in both Map3k1(ΔKD) and Lck(Cre/+)Map3k1(f/f) mice demonstrated that Mekk1 (encoded by Map3k1) signaling ... ...

Abstract	Mapks are important regulators of T cell proliferative expansion and cell cycle progression. Detailed genetic analysis of unconventional iNKT cells in both Map3k1(ΔKD) and Lck(Cre/+)Map3k1(f/f) mice demonstrated that Mekk1 (encoded by Map3k1) signaling activates Mapks to regulate Cdkn1b (encoding p27(Kip1)) expression and p27(Kip1)-dependent proliferative expansion in response to antigen. Mekk1 signaling and activation of E3 ubiquitin ligase Itch, by a phosphorylation-dependent conformational change, is also an important regulatory mechanism for the control of T helper cell cytokine production. Cdkn1b expression is regulated by Mekk1-dependent signaling in differentiated Th17 cells. Mekk1 is one of the 19 Ste11-like Map3ks, and Mekk1 signaling regulates iNKT cell proliferative expansion in response to glycolipid antigens and T cell homeostasis in the liver. Tak1 (encoded by Map3k7), a related Map3k to Mekk1, similarly regulates the proliferative expansion and homeostasis of T cells in the liver, and this illustrates the importance of multiple Map3ks for mammalian Mapk signaling.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Killer Cells, Natural/cytology ; Killer Cells, Natural/metabolism ; Liver/cytology ; MAP Kinase Kinase Kinase 1/metabolism ; MAP Kinase Kinase Kinases/genetics ; MAP Kinase Kinase Kinases/metabolism ; MAP Kinase Signaling System/genetics ; Mice, Inbred C57BL ; Models, Biological ; T-Lymphocytes/cytology ; T-Lymphocytes/enzymology
Chemical Substances	Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; MAP Kinase Kinase Kinase 1 (EC 2.7.11.25) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP kinase kinase kinase 7 (EC 2.7.11.25)
Language	English
Publishing date	2016-05-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2016.1189042
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Article: The PHD motif of Map3k1 activates cytokine-dependent MAPK signaling.

Gallagher, Ewen / Suddason, Tesha

Molecular & cellular oncology

2015 Volume 2, Issue 3, Page(s) e980659

Abstract: We generated a mutation in the gene encoding mitogen-activated protein kinase kinase kinase 1 (Map3k1) that results in a protein with an inactive plant homeodomain (PHD). Map3k1(mPHD) cells are defective in cytokine-mediated MAPK signaling. Protein array ...

Abstract	We generated a mutation in the gene encoding mitogen-activated protein kinase kinase kinase 1 (Map3k1) that results in a protein with an inactive plant homeodomain (PHD). Map3k1(mPHD) cells are defective in cytokine-mediated MAPK signaling. Protein array identified transforming growth factor (TGF-β)-activated kinase 1 binding protein 1 (Tab1) as a PHD substrate. The Map3k1 PHD transfers Lys63-linked poly-ubiquitin onto Tab1 to activate MAPKs.
Language	English
Publishing date	2015-05-06
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.4161/23723556.2014.980659
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Article ; Online: T-Cell-Specific Deletion of Map3k1 Reveals the Critical Role for Mekk1 and Jnks in Cdkn1b-Dependent Proliferative Expansion.

Suddason, Tesha / Anwar, Saba / Charlaftis, Nikolaos / Gallagher, Ewen

Cell reports

2016 Volume 14, Issue 3, Page(s) 449–457

Abstract: MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in Lck(Cre/+)Map3k1(f/f) mice, and these display larger ... ...

Abstract	MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in Lck(Cre/+)Map3k1(f/f) mice, and these display larger iNKT cell populations within the liver, spleen, and bone marrow. Mekk1 signaling controls splenic and liver iNKT cell expansion in response to glycolipid antigen. Lck(Cre/+)Map3k1(f/f) mice have enhanced liver damage in response to glycolipid antigen. Mekk1 regulates Jnk activation in iNKT cells and binds and transfers Lys63-linked poly-ubiquitin onto Carma1. Map3k1 is critical for the regulation of p27(Kip1) (encoded by Cdkn1b).
MeSH term(s)	Animals ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p27/genetics ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Galactosylceramides/immunology ; Galactosylceramides/pharmacology ; HEK293 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Liver/drug effects ; Liver/immunology ; Liver/metabolism ; Lymphocyte Activation/drug effects ; MAP Kinase Kinase Kinase 1/deficiency ; MAP Kinase Kinase Kinase 1/genetics ; MAP Kinase Kinase Kinase 1/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Natural Killer T-Cells/drug effects ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/metabolism ; Phosphorylation ; RNA/metabolism ; Spleen/drug effects ; Spleen/immunology ; Spleen/metabolism ; Ubiquitination
Chemical Substances	Cdkn1b protein, mouse ; Galactosylceramides ; alpha-galactosylceramide ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; RNA (63231-63-0) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinase 1 (EC 2.7.11.25) ; Map3k1 protein, mouse (EC 2.7.11.25)
Language	English
Publishing date	2016-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2015.12.047
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Article ; Online: T-Cell-Specific Deletion of Map3k1 Reveals the Critical Role for Mekk1 and Jnks in Cdkn1b-Dependent Proliferative Expansion

Tesha Suddason / Saba Anwar / Nikolaos Charlaftis / Ewen Gallagher

Cell Reports, Vol 14, Iss 3, Pp 449-

2016 Volume 457

Abstract: MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in LckCre/+ Map3k1f/f mice, and these display larger ... ...

Abstract	MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in LckCre/+ Map3k1f/f mice, and these display larger iNKT cell populations within the liver, spleen, and bone marrow. Mekk1 signaling controls splenic and liver iNKT cell expansion in response to glycolipid antigen. LckCre/+ Map3k1f/f mice have enhanced liver damage in response to glycolipid antigen. Mekk1 regulates Jnk activation in iNKT cells and binds and transfers Lys63-linked poly-ubiquitin onto Carma1. Map3k1 is critical for the regulation of p27Kip1 (encoded by Cdkn1b).
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Peripheral inflammatory pain sensitisation is independent of mast cell activation in male mice.

Lopes, Douglas M / Denk, Franziska / Chisholm, Kim I / Suddason, Tesha / Durrieux, Camille / Thakur, Matthew / Gentry, Clive / McMahon, Stephen B

Pain

2017 Volume 158, Issue 7, Page(s) 1314–1322

Abstract: The immune and sensory systems are known for their close proximity and interaction. Indeed, in a variety of pain states, a myriad of different immune cells are activated and recruited, playing a key role in neuronal sensitisation. During inflammatory ... ...

Abstract	The immune and sensory systems are known for their close proximity and interaction. Indeed, in a variety of pain states, a myriad of different immune cells are activated and recruited, playing a key role in neuronal sensitisation. During inflammatory pain it is thought that mast cells (MC) are one of the immune cell types involved in this process, but so far the evidence outlining their direct effect on neuronal cells remains unclear. To clarify whether MC are involved in inflammatory pain states, we used a transgenic mouse line (Mctp5Cre-iDTR) in which MC could be depleted in an inducible manner by administration of diphtheria toxin. Our results show that ablation of MC in male mice did not result in any change in mechanical and thermal hypersensitivity in the CFA model of inflammatory pain. Similarly, edema and temperature triggered by CFA inflammation at the injection site remained identical in MC depleted mice compared with their littermate controls. In addition, we show that Mctp5Cre-iDTR mice display normal levels of mechanical hypersensitivity after local injection of nerve growth factor (NGF), a factor well characterised to produce peripheral sensitisation and for being upregulated upon injury and inflammation. We also demonstrate that NGF treatment in vitro does not lead to an increased level of tumor necrosis factor-α in bone marrow-derived MC. Furthermore, our qRT-PCR data reveal that MC express negligible levels of NGF receptors, thereby explaining the lack of response to NGF. Together, our data suggest that MC do not play a direct role in peripheral sensitisation during inflammatory conditions.
MeSH term(s)	Animals ; Hyperalgesia/immunology ; Inflammation/immunology ; Inflammation/metabolism ; Male ; Mast Cells/drug effects ; Mast Cells/immunology ; Mast Cells/metabolism ; Mice ; Mice, Transgenic ; Nerve Growth Factor/pharmacology ; Pain/immunology ; Pain/metabolism ; Pain Measurement ; Pain Threshold/drug effects ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Tumor Necrosis Factor-alpha ; Nerve Growth Factor (9061-61-4)
Language	English
Publishing date	2017-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	193153-2
ISSN	1872-6623 ; 0304-3959
ISSN (online)	1872-6623
ISSN	0304-3959
DOI	10.1097/j.pain.0000000000000917
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Article ; Online: The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines.

Charlaftis, Nikolaos / Suddason, Tesha / Wu, Xuefeng / Anwar, Saba / Karin, Michael / Gallagher, Ewen

The EMBO journal

2014 Volume 33, Issue 21, Page(s) 2581–2596

Abstract: Unlike the other MAP3Ks, MEKK1 (encoded by Map3k1) contains a PHD motif. To understand the role of this motif, we have created a knockin mutant of mouse Map3k1 (Map3k1(m) (PHD)) with an inactive PHD motif. Map3k1(m) (PHD) ES cells demonstrate that the ... ...

Abstract	Unlike the other MAP3Ks, MEKK1 (encoded by Map3k1) contains a PHD motif. To understand the role of this motif, we have created a knockin mutant of mouse Map3k1 (Map3k1(m) (PHD)) with an inactive PHD motif. Map3k1(m) (PHD) ES cells demonstrate that the MEKK1 PHD controls p38 and JNK activation during TGF-β, EGF and microtubule disruption signalling, but does not affect MAPK responses to hyperosmotic stress. Protein microarray profiling identified the adaptor TAB1 as a PHD substrate, and TGF-β- or EGF-stimulated Map3k1(m) (PHD) ES cells exhibit defective non-canonical ubiquitination of MEKK1 and TAB1. The MEKK1 PHD binds and mediates the transfer of Lys63-linked poly-Ub, using the conjugating enzyme UBE2N, onto TAB1 to regulate TAK1 and MAPK activation by TGF-β and EGF. Both the MEKK1 PHD and TAB1 are critical for ES-cell differentiation and tumourigenesis. Map3k1(m) (PHD) (/+) mice exhibit aberrant cardiac tissue, B-cell development, testis and T-cell signalling.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Motifs ; Animals ; Cell Differentiation/physiology ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/metabolism ; Epidermal Growth Factor/genetics ; Epidermal Growth Factor/metabolism ; MAP Kinase Kinase 4/genetics ; MAP Kinase Kinase 4/metabolism ; MAP Kinase Kinase Kinase 1/genetics ; MAP Kinase Kinase Kinase 1/metabolism ; MAP Kinase Signaling System/physiology ; Mice ; Mice, Knockout ; Polyubiquitin/genetics ; Polyubiquitin/metabolism ; Protein Binding ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Ubiquitination/physiology ; p38 Mitogen-Activated Protein Kinases/genetics ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Tab1 protein, mouse ; Transforming Growth Factor beta ; Polyubiquitin (120904-94-1) ; Epidermal Growth Factor (62229-50-9) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinase 1 (EC 2.7.11.25) ; MAP Kinase Kinase 4 (EC 2.7.12.2)
Language	English
Publishing date	2014-09-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.201488351
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Article ; Online: MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival.

Steed, Emily / Elbediwy, Ahmed / Vacca, Barbara / Dupasquier, Sébastien / Hemkemeyer, Sandra A / Suddason, Tesha / Costa, Ana C / Beaudry, Jean-Bernard / Zihni, Ceniz / Gallagher, Ewen / Pierreux, Christophe E / Balda, Maria S / Matter, Karl

The Journal of cell biology

2014 Volume 204, Issue 5, Page(s) 821–838

Abstract: MarvelD3 is a transmembrane component of tight junctions, but there is little evidence for a direct involvement in the junctional permeability barrier. Tight junctions also regulate signaling mechanisms that guide cell proliferation; however, the ... ...

Abstract	MarvelD3 is a transmembrane component of tight junctions, but there is little evidence for a direct involvement in the junctional permeability barrier. Tight junctions also regulate signaling mechanisms that guide cell proliferation; however, the transmembrane components that link the junction to such signaling pathways are not well understood. In this paper, we show that MarvelD3 is a dynamic junctional regulator of the MEKK1-c-Jun NH2-terminal kinase (JNK) pathway. Loss of MarvelD3 expression in differentiating Caco-2 cells resulted in increased cell migration and proliferation, whereas reexpression in a metastatic tumor cell line inhibited migration, proliferation, and in vivo tumor formation. Expression levels of MarvelD3 inversely correlated with JNK activity, as MarvelD3 recruited MEKK1 to junctions, leading to down-regulation of JNK phosphorylation and inhibition of JNK-regulated transcriptional mechanisms. Interplay between MarvelD3 internalization and JNK activation tuned activation of MEKK1 during osmotic stress, leading to junction dissociation and cell death in MarvelD3-depleted cells. MarvelD3 thus couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival.
MeSH term(s)	Caco-2 Cells ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Cell Survival ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Kinase Kinase 1/metabolism ; MAP Kinase Signaling System ; Membrane Proteins/metabolism ; Membrane Proteins/physiology ; Osmotic Pressure ; Tight Junctions/metabolism
Chemical Substances	MARVELD3 protein, human ; Membrane Proteins ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinase 1 (EC 2.7.11.25) ; MAP3K1 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2014-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201304115
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Article: Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes.

Evans, Hayley G / Suddason, Tesha / Jackson, Ian / Taams, Leonie S / Lord, Graham M

Proceedings of the National Academy of Sciences of the United States of America

2007 Volume 104, Issue 43, Page(s) 17034–17039

Abstract: Recently, a new lineage of CD4+ T cells has been described in the mouse that specifically secretes IL-17 [T helper (Th) 17]. This discovery has led to a revision of the hypothesis that many autoimmune diseases are predominantly a Th1 phenomenon and may ... ...

Abstract	Recently, a new lineage of CD4+ T cells has been described in the mouse that specifically secretes IL-17 [T helper (Th) 17]. This discovery has led to a revision of the hypothesis that many autoimmune diseases are predominantly a Th1 phenomenon and may instead be critically dependent on the presence of Th17 cells. Murine Th17 cells differentiate from naïve T cell precursors in the presence of TGF-beta and IL-6 or IL-21. However, given their putative importance in human autoimmunity, very little is known about the pathways that control the expression of IL-17 in humans. Here we show that the factors that determine the expression of IL-17 in human CD4+ T cells are completely different from mice. IL-6 and IL-21 were unable to induce IL-17 expression in either naïve or effector T cells, and TGF-beta actually inhibited IL-17 expression. The expression of IL-17 was maximally induced from precommitted precursors present in human peripheral blood by cell-cell contact with Toll-like receptor-activated monocytes in the context of T cell receptor ligation. Furthermore, unlike IFN-gamma, IL-17 expression was not suppressed by the presence of FOXP3+ regulatory CD4+ T cells. Taken together, these data indicate that human and mouse Th17 cells have important biological differences that may be of critical importance in the development of therapeutic interventions in diseases characterized by aberrant T cell polarization.
MeSH term(s)	Cell Communication/drug effects ; Forkhead Transcription Factors/metabolism ; Humans ; Interleukin-17/immunology ; Interleukin-2 Receptor alpha Subunit/metabolism ; Interleukin-6/pharmacology ; Lymphocyte Activation ; Monocytes/cytology ; Monocytes/drug effects ; Monocytes/immunology ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes, Helper-Inducer/cytology ; T-Lymphocytes, Helper-Inducer/drug effects ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Regulatory/drug effects ; Th1 Cells/drug effects ; Th1 Cells/immunology ; Th2 Cells/drug effects ; Th2 Cells/immunology ; Toll-Like Receptors/immunology ; Transforming Growth Factor beta/pharmacology
Chemical Substances	FOXP3 protein, human ; Forkhead Transcription Factors ; Interleukin-17 ; Interleukin-2 Receptor alpha Subunit ; Interleukin-6 ; Receptors, Antigen, T-Cell ; Toll-Like Receptors ; Transforming Growth Factor beta
Language	English
Publishing date	2007-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0708426104
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Article ; Online: A central role for monocytes in Toll-like receptor-mediated activation of the vasculature.

Ward, Jon R / Francis, Sheila E / Marsden, Luke / Suddason, Tesha / Lord, Graham M / Dower, Steven K / Crossman, David C / Sabroe, Ian

Immunology

2009 Volume 128, Issue 1, Page(s) 58–68

Abstract: There is increasing evidence that activation of inflammatory responses in a variety of tissues is mediated co-operatively by the actions of more than one cell type. In particular, the monocyte has been implicated as a potentially important cell in the ... ...

Abstract	There is increasing evidence that activation of inflammatory responses in a variety of tissues is mediated co-operatively by the actions of more than one cell type. In particular, the monocyte has been implicated as a potentially important cell in the initiation of inflammatory responses to Toll-like receptor (TLR)-activating signals. To determine the potential for monocyte-regulated activation of tissue cells to underpin inflammatory responses in the vasculature, we established cocultures of primary human endothelial cells and monocytes and dissected the inflammatory responses of these systems following activation with TLR agonists. We observed that effective activation of inflammatory responses required bidirectional signalling between the monocyte and the tissue cell. Activation of cocultures was dependent on interleukin-1 (IL-1). Although monocyte-mediated IL-1beta production was crucial to the activation of cocultures, TLR specificity to these responses was also provided by the endothelial cells, which served to regulate the signalling of the monocytes. TLR4-induced IL-1beta production by monocytes was increased by TLR4-dependent endothelial activation in coculture, and was associated with increased monocyte CD14 expression. Activation of this inflammatory network also supported the potential for downstream monocyte-dependent T helper type 17 activation. These data define co-operative networks regulating inflammatory responses to TLR agonists, identify points amenable to targeting for the amelioration of vascular inflammation, and offer the potential to modify atherosclerotic plaque instability after a severe infection.
MeSH term(s)	Cell Communication/immunology ; Cell Survival/immunology ; Coculture Techniques ; Cytokines/biosynthesis ; Dose-Response Relationship, Immunologic ; Endothelial Cells/immunology ; Endothelium, Vascular/cytology ; Endothelium, Vascular/immunology ; Humans ; Inflammation/immunology ; Interleukin-1/biosynthesis ; Interleukin-1/immunology ; Lipopolysaccharide Receptors/metabolism ; Lipopolysaccharides/immunology ; Monocytes/immunology ; Signal Transduction/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; Toll-Like Receptor 2/agonists ; Toll-Like Receptors/immunology
Chemical Substances	Cytokines ; Interleukin-1 ; Lipopolysaccharide Receptors ; Lipopolysaccharides ; TLR2 protein, human ; Toll-Like Receptor 2 ; Toll-Like Receptors
Language	English
Publishing date	2009-08-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2009.03071.x
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Article: Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes

Evans, Hayley G / Suddason, Tesha / Jackson, Ian / Taams, Leonie S / Lord, Graham M

Proceedings of the National Academy of Sciences of the United States of America. 2007 Oct. 23, v. 104, no. 43

2007

Abstract: Recently, a new lineage of CD4⁺ T cells has been described in the mouse that specifically secretes IL-17 [T helper (Th) 17]. This discovery has led to a revision of the hypothesis that many autoimmune diseases are predominantly a Th1 phenomenon and may ... ...

Abstract	Recently, a new lineage of CD4⁺ T cells has been described in the mouse that specifically secretes IL-17 [T helper (Th) 17]. This discovery has led to a revision of the hypothesis that many autoimmune diseases are predominantly a Th1 phenomenon and may instead be critically dependent on the presence of Th17 cells. Murine Th17 cells differentiate from naïve T cell precursors in the presence of TGF-β and IL-6 or IL-21. However, given their putative importance in human autoimmunity, very little is known about the pathways that control the expression of IL-17 in humans. Here we show that the factors that determine the expression of IL-17 in human CD4⁺ T cells are completely different from mice. IL-6 and IL-21 were unable to induce IL-17 expression in either naïve or effector T cells, and TGF-β actually inhibited IL-17 expression. The expression of IL-17 was maximally induced from precommitted precursors present in human peripheral blood by cell-cell contact with Toll-like receptor-activated monocytes in the context of T cell receptor ligation. Furthermore, unlike IFN-γ, IL-17 expression was not suppressed by the presence of FOXP3⁺ regulatory CD4⁺ T cells. Taken together, these data indicate that human and mouse Th17 cells have important biological differences that may be of critical importance in the development of therapeutic interventions in diseases characterized by aberrant T cell polarization.
Language	English
Dates of publication	2007-1023
Size	p. 17034-17039.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Bonn / Germany

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Inter-library loan at ZB MED