Sex-specific adipose tissue imprinting of regulatory T cells

Vasanthakumar, Ajithkumar; Chisanga, David; Blume, Jonas; Gloury, Renee; Britt, Kara; Henstridge, Darren C.; Zhan, Yifan; Torres, Santiago Valle; Liene, Sebastian; Collins, Nicholas; Cao, Enyuan; Sidwell, Tom; Li, Chaoran; Spallanzani, Raúl G.; Liao, Yang; Beavis, Paul A.; Gebhardt, Thomas; Trevaskis, Natalie L.; Nutt, Stephen L.; Zajac, Jeffrey D; Davey, Rachel A; Febbraio, Mark A.; Mathis, Diane; Shi, Wei; Kallies, Axel

doi:10.1038/s41586-020-2040-3

Cited by 158 publications

(255 citation statements)

References 44 publications

Supporting

Mentioning

238

Contrasting

Order By: Relevance

“…Likewise, testosterone treatment in female mice expanded CD73 + stromal cells, which was associated with expansion of the VAT-Treg population. 43 These observations support the notion that sex hormones influence the function of VmSC subtypes and this, in turn, might set niche-specific characteristics, most notably IL-33 availability ( Figure 3B).…”

Section: Sexsupporting

confidence: 82%

“…Correspondingly, estrogen administration was associated with reduced Il6 and Ccl2 transcript levels within VAT, resulting in less Treg accumulation. 43 Although the precise cellular target of estrogen is unknown, mSCs are likely to be involved, as previous evidence indicated that a subset of VAT stromal cells (CD45 − CD31 − CD29 + CD34 + Sca-1 + CD24 − ) is a relevant source of CCL2 upon high-fat feeding. 66 In contrast, male mice lacking androgen receptor gene (Ar) expression, exhibited fewer IL-33-producing CD73 + stromal cells, paired with lower numbers of VAT Tregs compared with their wildtype counterparts.…”

Section: Sexmentioning

confidence: 99%

“…14 In addition, when Tregs from female vTreg53 TCR-tg mice are transferred into female wildtype recipients, they accumulate less in gonadal VAT and express much lower levels of ST2 than is the case when Tregs from males are transferred into male recipients. 43 Within males, there is also a reduction in Tregs and their ST2 expression in inguinal SAT compared with gonadal VAT. 4,14 The sex and depot dimorphisms of VAT Tregs can potentially be explained by different compositions of IL-33-expressing stromal cells, which were significantly reduced in female gonadal VAT or inguinal SAT from both genders compared with male gonadal VAT.…”

Section: Sex and Depotmentioning

confidence: 99%

“…14,27 The mechanisms underlying the differential representation of IL-33expressing stromal cells in males versus females are not completely known but could be caused by signaling through the sex hormone receptors. 27,43 In addition, a basal heightened inflammatory state in male gonadal VAT may also drive the preferential accumulation of VAT Tregs 43 (see below for more details). Consistent with this scenario, VAT Tregs in females, but not in males, are increased in response to weight gain by HFD treatment.…”

Section: Sex and Depotmentioning

confidence: 99%

See 3 more Smart Citations

Visceral adipose tissue Tregs and the cells that nurture them

Spallanzani

Mathis

2020

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

Visceral adipose tissue (VAT) is a primary site for storage of excess energy, but it also serves as an important endocrine organ that impacts organismal metabolism. Chronic, low-grade inflammation of VAT, and eventually systemically, is one of the major drivers of obesity-associated insulin resistance and metabolic abnormalities. A unique population of regulatory T cells (Tregs), with a distinct transcriptional profile and antigen receptor repertoire resides in VAT, keeps inflammation in check and regulates organismal metabolism. Accumulation of these cells depends on interactions with other local immunocytes and, importantly, subtypes of VAT mesenchymal stromal cells (VmSCs) that are either immunomodulators or adipogenic. We summarize our current understanding of the phenotype, function, dependencies, derivation, and modulations of VAT Tregs, and review the heterogeneity and regulation of VmSCs as well as their cross talk with VAT Tregs. Lastly, we discuss imperative questions remaining to be answered. K E Y W O R D Sadipose tissue obesity, IL-33, immunometabolism, mesenchymal stromal cells, Treg cells

show abstract

Section: Sexsupporting

confidence: 82%

Section: Sexmentioning

confidence: 99%

Section: Sex and Depotmentioning

confidence: 99%

Section: Sex and Depotmentioning

confidence: 99%

See 2 more Smart Citations

Visceral adipose tissue Tregs and the cells that nurture them

Spallanzani

Mathis

2020

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

show abstract

“…In particular, the expression of CCR2 was higher in male VAT Tregs compared to female Tregs. Female mice treated with testosterone showed an increased VAT expression of CCL2, the ligand for CCR2, and IL-6 and IL1ß, which likely stem from innate immune cells (92). These data show that the microenvironment including crosstalk with epithelial and innate immune cells clearly contributes to sex dependent differences observed in T cells.…”

Section: Effects Of Testosterone On T Cells In Animal Modelsmentioning

confidence: 67%

The Effects of Androgens on T Cells: Clues to Female Predominance in Autoimmune Liver Diseases?

2020

View full text Add to dashboard Cite

The immune system responds differently in women and in men. Generally speaking, adult females show stronger innate and adaptive immune responses than males. This results in lower risk of developing most of the infectious diseases and a better ability to clear viral infection in women (1-5). On the other hand, women are at increased risk of developing autoimmune diseases (AID) such as rheumatoid arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren's syndrome, and the autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) (6). Factors contributing to the female sex bias in autoimmune diseases include environmental exposure, e.g., microbiome, behavior, and genetics including X chromosomal inactivation of genes. Several lines of evidence and clinical observations clearly indicate that sex hormones contribute significantly to disease pathogenesis, and the role of estrogen in autoimmune diseases has been extensively studied. In many of these diseases, including the autoimmune liver diseases, T cells are thought to play an important pathogenetic role. We will use this mini-review to focus on the effects of androgens on T cells and how the two major androgens, testosterone and dihydrotestosterone, potentially contribute to the pathogenesis of autoimmune liver diseases (AILD).

show abstract