Sodium chloride is an ionic checkpoint for human Th2 cell responses and shapes the atopic skin microenvironment

One sentence summarySodium is an ionic checkpoint for the induction and amplification of human Th2 cell responses and shapes the atopic skin microenvironment, where it could serve as a novel therapeutic target for Th2 mediated diseases.AbstractThere has been a strong increase in the incidence of allergic diseases over the last 50 years. Environmental factors most likely account for this phenomenon. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation, which is characteristic of atopic diseases, remains unclear. It has previously been reported that dietary sodium chloride promotes the polarization of Th17 cells with implications for autoimmune diseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potently promotes Th2 cell responses on multiple regulatory levels. Sodium chloride enhanced IL-4 and IL-13 production while suppressing IFN-γproduction in effector T cells. It diverted alternative T cell fates into the Th2 cell phenotype and also inducedde novoTh2 cell polarization from naïve T cell precursors. Mechanistically, it exerted its effects via the osmosensitive transcription factor NFAT-5 and the kinase SGK-1, which regulated Th2 signature cytokines and master transcription factors in hyperosmolar salt conditions. The skin of patients suffering from atopic dermatitis contained highly elevated amounts of sodium compared to non-lesional atopic and healthy skin. This demonstrates that sodium chloride represents a so far overlooked cutaneous microenvironmental factor in atopic dermatitis that can induce Th2 cell responses, the orchestrators of allergic diseases. Together, our data propose ionic signaling through sodium chloride as a novel checkpoint and potential therapeutic target for type 2 immunity and its associated allergic diseases.

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Sodium chloride is an ionic checkpoint for human TH2 cells and shapes the atopic skin microenvironment

Science Translational Medicine ◽

10.1126/scitranslmed.aau0683 ◽

2019 ◽

Vol 11 (480) ◽

pp. eaau0683 ◽

Cited By ~ 14

Author(s):

Julia Matthias ◽

Julia Maul ◽

Rebecca Noster ◽

Hanna Meinl ◽

Ying-Yin Chao ◽

...

Keyword(s):

Atopic Dermatitis ◽

T Cell ◽

Sodium Chloride ◽

Cell Polarization ◽

Dietary Sodium ◽

Interleukin 4 ◽

Th2 Cells ◽

Cell Phenotype ◽

Atopic Diseases ◽

Cell Responses

The incidence of allergic diseases has increased over the past 50 years, likely due to environmental factors. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation characteristic of atopic diseases remain unclear. It has previously been reported that dietary sodium chloride promotes the polarization of T helper 17 (TH17) cells with implications for autoimmune diseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potently promotes TH2 cell responses on multiple regulatory levels. Sodium chloride enhanced interleukin-4 (IL-4) and IL-13 production while suppressing interferon-γ (IFN-γ) production in memory T cells. It diverted alternative T cell fates into the TH2 cell phenotype and also induced de novo TH2 cell polarization from naïve T cell precursors. Mechanistically, sodium chloride exerted its effects via the osmosensitive transcription factor NFAT5 and the kinase SGK-1, which regulated TH2 signature cytokines and master transcription factors in hyperosmolar salt conditions. The skin of patients suffering from atopic dermatitis contained elevated sodium compared to nonlesional atopic and healthy skin. These results suggest that sodium chloride represents a so far overlooked cutaneous microenvironmental checkpoint in atopic dermatitis that can induce TH2 cell responses, the orchestrators of atopic diseases.

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Type 2 Helper T-Cell Cytokines Induce Morphologic and Molecular Characteristics of Atopic Dermatitis in Human Skin Equivalent

American Journal Of Pathology ◽

10.1016/j.ajpath.2011.01.037 ◽

2011 ◽

Vol 178 (5) ◽

pp. 2091-2099 ◽

Cited By ~ 34

Author(s):

Marijke Kamsteeg ◽

Mieke Bergers ◽

Roelie de Boer ◽

Patrick L.J.M. Zeeuwen ◽

Stanleyson V. Hato ◽

...

Keyword(s):

Atopic Dermatitis ◽

T Cell ◽

Human Skin ◽

Skin Equivalent ◽

Molecular Characteristics ◽

Helper T Cell ◽

Human Skin Equivalent

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Regulation of T Cell Responses by Ionic Salt Signals

Cells ◽

10.3390/cells10092365 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2365

Author(s):

Christina E. Zielinski

Keyword(s):

T Cells ◽

T Cell ◽

Sodium Chloride ◽

T Cell Responses ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Tissue Microenvironment ◽

Cell Responses ◽

The Impact

T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.

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Metabolic Interdependency of Th2 Cell-Mediated Type 2 Immunity and the Tumor Microenvironment

Frontiers in Immunology ◽

10.3389/fimmu.2021.632581 ◽

2021 ◽

Vol 12 ◽

Author(s):

Simon Schreiber ◽

Christoph M. Hammers ◽

Achim J. Kaasch ◽

Burkhart Schraven ◽

Anne Dudeck ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Allergic Diseases ◽

Building Blocks ◽

Th2 Cells ◽

Th Cells ◽

Th2 Cell ◽

Type 2 Immunity ◽

Mediate Immunity

The function of T cells is critically dependent on their ability to generate metabolic building blocks to fulfil energy demands for proliferation and consecutive differentiation into various T helper (Th) cells. Th cells then have to adapt their metabolism to specific microenvironments within different organs during physiological and pathological immune responses. In this context, Th2 cells mediate immunity to parasites and are involved in the pathogenesis of allergic diseases including asthma, while CD8+ T cells and Th1 cells mediate immunity to viruses and tumors. Importantly, recent studies have investigated the metabolism of Th2 cells in more detail, while others have studied the influence of Th2 cell-mediated type 2 immunity on the tumor microenvironment (TME) and on tumor progression. We here review recent findings on the metabolism of Th2 cells and discuss how Th2 cells contribute to antitumor immunity. Combining the evidence from both types of studies, we provide here for the first time a perspective on how the energy metabolism of Th2 cells and the TME interact. Finally, we elaborate how a more detailed understanding of the unique metabolic interdependency between Th2 cells and the TME could reveal novel avenues for the development of immunotherapies in treating cancer.

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Staphylococcus aureus proteoglycans can limit type 2 T cell differentiation: Implications for atopic dermatitis

10.22541/au.158921553.30663436 ◽

2020 ◽

Author(s):

Vladimir Gim nez Rivera ◽

Adam Peres ◽

Gaurav Isola ◽

Denis Sasseville ◽

Robert Bissonnette ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Atopic Dermatitis ◽

Cell Differentiation ◽

T Cell ◽

T Cell Differentiation

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Type 1 or Type 2 T Cell Responses

Encyclopedic Reference of Immunotoxicology ◽

10.1007/3-540-27806-0_1528 ◽

2006 ◽

pp. 677-678

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cell Responses

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T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1522287113 ◽

2016 ◽

Vol 113 (5) ◽

pp. E568-E576 ◽

Cited By ~ 10

Author(s):

Jimena Perez-Lloret ◽

Isobel S. Okoye ◽

Riccardo Guidi ◽

Yashaswini Kannan ◽

Stephanie M. Coomes ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Allergic Diseases ◽

Treg Cells ◽

Th2 Cells ◽

T Helper 2 ◽

Cytokines And Chemokines ◽

Th2 Cell

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

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