Histamine suppresses regulatory <scp>T</scp> cells mediated by <scp>TGF</scp>‐<i>β</i> in murine chronic allergic contact dermatitis

Tamaka, Kyoko; Seike, Masahiro; Hagiwara, Takaaki; Satō, Atsushi; Ohtsu, Hiroshi

doi:10.1111/exd.12644

Cited by 16 publications

(16 citation statements)

References 28 publications

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“…3f). As histamine has been implicated in suppressing T reg cell function 19 , an increased production of histamine in LKB-deficient T reg cells could contribute to their defects in an autocrine manner. Metabolite set enrichment analysis indicated that LKB1 deficiency in T reg cells downregulated multiple metabolic programs, but upregulated the pathway for biosynthesis of unsaturated fatty acids (Fig.…”

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confidence: 99%

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

Yang

Blanco

Neale

et al. 2017

Nature

154

150

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Regulatory T cells (Treg cells) play a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis1,2. Transcriptional programming of regulatory mechanisms facilitates Treg cell functional activation in the prevention of diverse types of inflammatory responses3,4. How Treg cells orchestrate their homeostasis and interplay with environmental signals remains poorly understood. Here we show that liver kinase B1 (LKB1) programs proper metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis. Mice with Treg-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive TH2-dominant responses. LKB1 deficiency disrupted Treg cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1, and TNF receptor (TNRF) superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in Treg cells was independent of conventional AMPK signaling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signaling for the proper control of PD-1 and TNFR proteins. Blockade of PD-1 activity reinvigorated the suppressive capability of LKB1-deficient Treg cells in the repression of TH2 responses and the interplay with thymic stromal lymphopoietin (TSLP)-primed dendritic cells (DCs). Thus, Treg cells employ LKB1 signaling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.

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confidence: 99%

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

Yang

Blanco

Neale

et al. 2017

Nature

154

150

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“…[24,25] Tamaka et al have reported that recombinant TGF-β1 injection promoted the infiltration of Tregs in the skin, and anti-TGF-β1 antibody injection suppressed the number of Tregs in the skin in mice with chronic allergic contact dermatitis. [26] These findings suggest that TGF-β is important for Treg induction in the inflammatory and immune responses including the skin.…”

Section: Discussionmentioning

confidence: 95%

“…Through the co‐stimulation of the T‐cell receptor (TCR) and TGF‐β signalling, Treg production can be induced or Tregs can be converted from peripheral CD4 + CD25 ‐ naive responder T cells via the expression of the gene for the Foxp3 transcription factor . Tamaka et al have reported that recombinant TGF‐β1 injection promoted the infiltration of Tregs in the skin, and anti‐TGF‐β1 antibody injection suppressed the number of Tregs in the skin in mice with chronic allergic contact dermatitis . These findings suggest that TGF‐β is important for Treg induction in the inflammatory and immune responses including the skin.…”

Section: Discussionmentioning

confidence: 99%

Platelets are important for the development of immune tolerance: Possible involvement of TGF‐β in the mechanism

Hotta

Tamagawa‐Mineoka

Katoh

2019

Experimental Dermatology

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Platelets have diverse roles in immune processes in addition to their key functions in haemostasis and thrombosis. Some studies imply that platelets may be possibly related to the immune tolerance induction. However, the role of platelets in the development of immune tolerance is not fully understood. The purpose of this study was to investigate the role of platelets in the development of regulatory mechanisms responsible for cutaneous inflammation using a mouse model of low zone tolerance (LZT). Mice were treated with 2,4,6‐trinitro‐1‐chlorobenzene (TNCB) 8 times every other day for tolerance induction with administration of anti‐platelet antibody or control antibody during the tolerance induction phase every 3 days. After the treatment for the tolerance induction, mice were sensitized and then challenged with TNCB. The contact hypersensitivity (CHS) was significantly decreased at 24 hours after challenge in the mice with LZT than in those without LZT. Platelet depletion via administration of anti‐platelet antibody reversed the inhibition of CHS and reduced the frequency of Foxp3+ Tregs in the inflamed skin and draining lymph nodes in mice with LZT. In addition, repeated low‐dose skin exposure resulted in elevated plasma levels of transforming growth factor (TGF)‐β1. Interestingly, platelet depletion reduced plasma TGF‐β1 levels of mice with LZT. Furthermore, the CHS response was reduced by administration of recombinant TGF‐β1 during platelet depletion in mice with LZT. Administration of anti‐TGF‐β antibody reversed the inhibition of the CHS responses. These results suggest that platelets are involved in the induction of immune tolerance via the release of TGF‐β1.

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“…Interestingly, allergic responses of CACD (epidermal hyperplasia, dense infiltration of inflammatory cells, and elevated levels of inflammatory cytokines and IgE) are ameliorated during excessive, repeated exposure to the same allergen [52] . As the levels of TGF-β and IL-10 are elevated in CACD [52,53] , allergic responses are considered to be suppressed by Tregs.…”

Section: Allergic Contact Dermatitis and Regulatory T Cellsmentioning

confidence: 99%

Regulatory T Cells and Histamine in Allergic Contact Dermatitis

Seike¹

2019

Journal of Dermatological Research

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Regulatory T cells (Tregs) are crucial in preventing excessive immune responses and autoimmunity. Tregs elicit a direct or indirect response on target cells (such as lymphocytes, dendritic cells, monocytes, and mast cells). In allergic contact dermatitis and its animal model contact hypersensitivity, Tregs suppress sensitization and elicitation of delayed-type hypersensitivity responses to allergens. Chronic allergic contact dermatitis (CACD) induced by repeated exposure of the skin to the same allergen bears clinical, histological and immunological similarities with those of atopic dermatitis. Allergic responses of CACD are ameliorated as a result of infiltration of Tregs and elevation of IL-10 and transforming growth factor-beta1 (TGF-β1) levels. In CACD, histamine suppresses Tregs infiltration and IL-10 production by decreasing the TGF-β1 levels through histamine H1 and H4 receptors. As a result, histamine amplifies eczema and maintains allergic reactions in CACD.

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Histamine suppresses regulatory T cells mediated by TGF‐β in murine chronic allergic contact dermatitis

Cited by 16 publications

References 28 publications

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling

Platelets are important for the development of immune tolerance: Possible involvement of TGF‐β in the mechanism

Regulatory T Cells and Histamine in Allergic Contact Dermatitis

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