Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell–mediated inflammation in the skin

Takahashi, Hayato; Nomura, Hiroyuki; Iriki, Hisato; Kubo, Akiharu; Isami, Koichi; Mikami, Yohei; Mukai, Masayuki; Sasaki, Takayuki; Yamagami, Jun; Kudoh, Jun; Ito, Hiromi; Kamata, Aki; Kurebayashi, Yutaka; Yoshida, Hiroki; Yoshimura, Akihiko; Sun, Hui; Suematsu, Makoto; O’Shea, John J.; Kanno, Yuka; Amagai, Masayuki

doi:10.1126/sciimmunol.abb6444

Cited by 13 publications

(10 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This transgenic system helped elucidate several novel immunological findings associated with T cell-mediated autoimmune responses, such as the essential roles of IFNγ-and the immunoregulatory function of Langerhans cells and cholesterol 25-hydroxylase expressed in CD4 + T cells in interface dermatitis. [42][43][44] The experimental models for pemphigus discussed here have contributed to our deeper understanding of disease pathogenesis and the potential of new therapeutic strategies.…”

Section: Animal Model Of Cellular Autoimmunity Against Dsg3mentioning

confidence: 99%

“…On the other hand, when Dsg3‐specific CD4 + transgenic T cells developed in the absence of Dsg3, they were able to induce anti‐Dsg3 antibody production and acantholysis in histology as well as interface dermatitis after the adoptive transfer into Rag2 −/− mice together with Dsg3 −/− B cells, demonstrating the potential of Dsg3‐specific T cells to induce both interface dermatitis and acantholysis (Figure 1). This transgenic system helped elucidate several novel immunological findings associated with T cell‐mediated autoimmune responses, such as the essential roles of IFN‐γ‐and the immunoregulatory function of Langerhans cells and cholesterol 25‐hydroxylase expressed in CD4 + T cells in interface dermatitis 42–44 …”

Section: Animal Model Of Pemphigusmentioning

confidence: 99%

“…This transgenic system helped elucidate several novel immunological findings associated with T cell‐mediated autoimmune responses, such as the essential roles of IFN‐γ‐and the immunoregulatory function of Langerhans cells and cholesterol 25‐hydroxylase expressed in CD4 + T cells in interface dermatitis. 42 , 43 , 44 …”

Section: Animal Model Of Pemphigusmentioning

confidence: 99%

See 2 more Smart Citations

T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen

Takahashi

Iriki

Asahina

2022

The Journal of Dermatology

Self Cite

View full text Add to dashboard Cite

Pemphigus is a life‐threatening autoimmune bullous disease mediated by anti‐desmoglein IgG autoantibodies. Pemphigus is mainly classified into three subtypes: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. The pathogenicity of autoantibodies has been extensively studied. Anti‐human CD20 antibody therapy targeting B cells emerged as a more effective treatment option compared to conventional therapy for patients with an intractable disease. On the other hand, autoreactive T cells are considered to be involved in the pathogenesis based on the test results of human leukocyte antigen association, autoreactive T cell detection, and cytokine profile analysis. Research on the role of T cells in pemphigus has continued to progress, including that on T follicular helper cells, which initiate molecular mechanisms involved in antibody production in B cells. Autoreactive T cell research in mice has highlighted the crucial roles of cellular autoimmunity and improved the understanding of its pathogenesis, especially in paraneoplastic pemphigus. The mouse research has helped elucidate novel regulatory mechanisms of autoreactive T cells, such as thymic tolerance to desmoglein 3 and the essential roles of regulatory T cells, Langerhans cells, and other molecules in peripheral tissues. This review focuses on the immunological aspects of autoreactive T cells in pemphigus by providing detailed information on various related topics.

show abstract

Section: Animal Model Of Cellular Autoimmunity Against Dsg3mentioning

confidence: 99%

Section: Animal Model Of Pemphigusmentioning

confidence: 99%

Section: Animal Model Of Pemphigusmentioning

confidence: 99%

See 1 more Smart Citation

T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen

Takahashi

Iriki

Asahina

2022

The Journal of Dermatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, it is clear that 25HC has immunomodulatory functions 47–49 . Thus, it may be that 25HC accumulation in locally inflamed tissues might serve as a metabolic regulator of T cell responses through its ability to influence mevalonate metabolism of responding T cell 50 …”

Section: Regulation Of the Mevalonate Pathwaymentioning

confidence: 99%

Decoding the crosstalk between mevalonate metabolism and T cell function

Kennewick

Bensinger

2023

Immunological Reviews

View full text Add to dashboard Cite

SummaryThe mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function. Accordingly, there is tight regulatory control over metabolic flux through the branches of this essential lipid synthetic pathway. In this review we provide an overview of how the branches of the mevalonate pathway are regulated in T cells and discuss our current understanding of the relationship between mevalonate metabolism, cholesterol homeostasis and T cell function.

show abstract

“…119 Similarly, 25-HC produced by CD4 + T cells may dampen the progress of skin inflammation, suggesting its role in the expression of persistence and exacerbation of allergic inflammation. 120 Recent evidence also suggests that Tfam fl/fl CD4-Cre mice exhibit a higher production of inflammatory cytokines (TNF) and the significant upregulation of senescent-associated genes in the liver, heart, white adipose tissue, and pancreas due to the metabolic dysfunction. 91 Similarly, the activity of senescence-associated βgalactosidase is also elevated, suggesting that the aberrant metabolism of T cells accelerates organismal dyshomeostasis.…”

Section: Cholesterol In T-cell Senescencementioning

confidence: 99%

Cholesterol metabolism in T‐cell aging: Accomplices or victims

Zhu

et al. 2023

The FASEB Journal

View full text Add to dashboard Cite

Aging has a significant impact on the function and metabolism of T cells. Cholesterol, the most important sterol in mammals, is known as the “gold of the body” because it maintains membrane fluidity, rigidity, and signal transduction while also serving as a precursor of oxysterols, bile acids, and steroid hormones. Cholesterol homeostasis is primarily controlled by uptake, biosynthesis, efflux, and regulatory mechanisms. Previous studies have suggested that there are reciprocal interactions between cholesterol metabolism and T lymphocytes. Here, we will summarize the most recent advances in the effects of cholesterol and its derivatives on T‐cell aging. We will furthermore discuss interventions that might be used to help older individuals with immune deficiencies or diminishing immune competence.

show abstract

Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell–mediated inflammation in the skin

Abstract: CD4 + T cells limit pathogenic bystander T cell expansion by suppressing cholesterol biosynthesis via secreted 25-hydroxycholesterol.

Cited by 13 publications

References 55 publications

T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen

T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen

Decoding the crosstalk between mevalonate metabolism and T cell function

Cholesterol metabolism in T‐cell aging: Accomplices or victims

Contact Info

Product

Resources

About