Conditional Deletion of TAK1 in T Cells Reveals a Pivotal Role of TCRαβ+ Intraepithelial Lymphocytes in Preventing Lymphopenia-Associated Colitis

Sanjo, Hideki; Tokumaru, Shigeo; Akira, Shizuo; Taki, Shinsuke

doi:10.1371/journal.pone.0128761

Cited by 9 publications

(8 citation statements)

References 38 publications

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“…Analysis of Tak1 fl/fl Cd4 Cre mice confirmed the selective absence CD8αα IELs, but not TCRγδ + IELs in the small intestine ( Fig. 1c ), as previously reported 10 . Correspondingly, we observed a reduction of CD122 + H-2K b+ DN thymocytes in TAK1-deficient mice ( Fig.…”

Section: Resultssupporting

confidence: 89%

CD8αα intraepithelial lymphocytes arise from two main thymic precursors

et al. 2017

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TCRαβ+ CD8αα+ intestinal intraepithelial lymphocytes (CD8αα IELs) are an abundant population of thymus-derived T cells that protect the gut barrier surface. We sought to better define the thymic IEL precursor (IELp) by analysis of their maturation, localization, and emigration. We defined two precursors among TCRβ+CD4–CD8– thymocytes using TAK1 dependence and rigorous lineage-exclusion criteria. Those IELp populations include a nascent PD-1+ population and a T-bet+ population that accumulated with age. Both gave rise to intestinal CD8αα IELs upon adoptive transfer. PD-1+ cells contained more strongly self-reactive clones and were largely classical MHC restricted. They localized to the cortex, and efficiently emigrated in an S1PR1-dependent manner. T-bet+ IELp localized to the medulla, included non-classical MHC-restricted cells and expressed NK1.1, CD103 and CXCR3. The two IELp populations further differed in TCR Vα and Vβ usage. These data provide an important foundation for understanding the biology of CD8αα IELs.

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Section: Resultssupporting

confidence: 89%

CD8αα intraepithelial lymphocytes arise from two main thymic precursors

et al. 2017

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“…Previous work has supported the regulatory role of TAK1 in the production of cytokines including IL‐6 in murine embryonic fibroblasts 45 . Inhibition and inactivation of TAK1 has also been shown to impair cytotoxicity and cytokine and chemokine production in NK cells 63 ; on the other hand T cell‐specific knockout of TAK1 has resulted in an increase in the gene expression of IL‐6 and TNF among other pro‐inflammatory cytokines 64 . Inhibition of this spectrum of cytokines to the degree we detect is particularly supportive of the potential utility of targeting TAK1 activity therapeutically to down‐regulate allergic inflammation caused by activated mast cells.…”

Section: Discussionmentioning

confidence: 91%

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Watson

Maguire

Rouillard

et al. 2020

Journal of Leukocyte Biology

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Mast cells drive the inappropriate immune response characteristic of allergic inflammatory disorders via release of pro‐inflammatory mediators in response to environmental cues detected by the IgE‐FcεRI complex. The role of TGF‐β‐activated kinase 1 (TAK1), a participant in related signaling in other contexts, remains unknown in allergy. We detect novel activation of TAK1 at Ser412 in response to IgE‐mediated activation under SCF‐c‐kit potentiation in a mast cell‐driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor 5Z‐7‐oxozeaenol (OZ). We, therefore, interrogated the role of TAK1 in a series of mast cell‐mediated responses using IgE‐sensitized murine bone marrow‐derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition by OZ resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NF‐κB pathway via IκBα. Impaired gene expression and near abrogation in release of pro‐inflammatory cytokines TNF, IL‐6, IL‐13, and chemokines CCL1, and CCL2 was detected. Finally, a significant inhibition of mast cell degranulation, accompanied by an impairment in calcium mobilization, was observed in TAK1‐inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NF‐κB pathways in driving the late‐phase response, but also initiation of the degranulation mechanism of the mast cell early‐phase response following allergen recognition and may warrant consideration in future therapeutic development.

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“…The same group later found that in these mice TAK1 expression is retained in CD4 + T-cells. These cells acquire an inflammatory phenotype and continuous access to colon that result in pathogenesis in colitis (Sanjo et al 2015). Also, TAK1 in epithelial cells was protective in mouse colitis (Kajino-Sakamoto et al 2008;Kim et al 2009).…”

Section: Introductionmentioning

confidence: 99%

“…These cells acquire an inflammatory phenotype and continuous access to colon that result in pathogenesis in colitis (Sanjo et al. ). Also, TAK1 in epithelial cells was protective in mouse colitis (Kajino‐Sakamoto et al.…”

Section: Introductionmentioning

confidence: 99%

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

et al. 2017

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The etiology and mechanisms for inflammatory bowel disease (IBD) are incompletely known. Determination of new, clinically important mechanisms for intestinal inflammation is imperative for developing effective therapies to treat IBD. We sought to define a widespread mechanism for colon mucosal inflammation via the activation of TGF‐β activated Kinase 1 (TAK1), a central regulator of cellular inflammatory actions. Activation of TAK1 and the downstream inflammatory signaling mediators was determined in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD) as well as in DSS‐induced and spontaneous IBD in mice. The role of TAK1 in facilitating intestinal inflammation in murine models of IBD was investigated by using (5Z)‐7‐Oxozeaenol, a highly selective pharmacological inhibitor of TAK1. We found hyper‐activation of TAK1 in patients with UC or CD and in murine models of IBD. Pharmacological inhibition of TAK1 prevented loss in body weight, disease activity, microscopic histopathology, infiltration of inflammatory cells in the colon mucosa, and elevated proinflammatory cytokine production in two murine models of IBD. We demonstrated that at the early phase of the disease activation of TAK1 is restricted in the epithelial cells. However, at a more advanced stage of the disease, TAK1 activation predominantly occurs in nonepithelial cells, especially in macrophages. These findings elucidate the activation of TAK1 as crucial in promoting intestinal inflammation. Thus, the TAK1 activation pathway may represent a suitable target to design new therapies for treating IBD in humans.

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Conditional Deletion of TAK1 in T Cells Reveals a Pivotal Role of TCRαβ+ Intraepithelial Lymphocytes in Preventing Lymphopenia-Associated Colitis

Cited by 9 publications

References 38 publications

CD8αα intraepithelial lymphocytes arise from two main thymic precursors

CD8αα intraepithelial lymphocytes arise from two main thymic precursors

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

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