Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study

Robinson, George; Peng, Junjie; Peckham, Hannah; Butler, Gary; Pineda‐Torra, Inés; Ciurtin, Coziana; Jury, Elizabeth C.

doi:10.1016/s2665-9913(22)00198-9

Cited by 23 publications

(16 citation statements)

References 34 publications

(47 reference statements)

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“…It has been proposed that immune responsiveness differs between males and females probably reflecting higher frequencies of Tregs in males. [42][43][44] To address this issue in PSC, we reanalyzed our findings separately in male and female patients but observed similar changes in either sex. However, the greatest differences to healthy controls were observed in male patients with PSC (Supporting Information S3: Figure 3).…”

Section: Resultsmentioning

confidence: 99%

STAT activation in regulatory CD4⁺ T cells of patients with primary sclerosing cholangitis

Dold,

Kalthoff,

Frank

et al. 2024

Immunity Inflam & Disease

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IntroductionRegulatory CD4+ T cells (Tregs) are pivotal for inhibition of autoimmunity. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology where contribution of Tregs is still unclear. Activation of the JAK‐STAT pathway critically modifies functions of Tregs. In PSC, we studied activation of STAT proteins and Treg functions in response to cytokines.MethodsIn 51 patients with PSC, 10 disease controls (chronic replicative hepatitis C), and 36 healthy controls we analyzed frequencies of Foxp3+CD25+CD127lowCD4+ Tregs, their expression of ectonucleotidase CD39, and cytokine‐induced phosphorylation of STAT1, 3, 5, and 6 using phospho‐flow cytometry. In parallel, we measured cytokines IFN‐gamma, interleukin (IL)‐6, IL‐2, and IL‐4 in serum via bead‐based immunoassays.ResultsIn patients with PSC, ex vivo frequencies of peripheral Tregs and their expression of CD39 were significantly reduced (p < .05 each). Furthermore, serum levels of IFN‐gamma, IL‐6, IL‐2, and IL‐4 were markedly higher in PSC (p < .05 each). Unlike activation of STAT1, STAT5, and STAT6, IL‐6 induced increased phosphorylation of STAT3 in Tregs of PSC‐patients (p = .0434). Finally, STAT3 activation in Tregs correlated with leukocyte counts.ConclusionsIn PSC, we observed enhanced STAT3 responsiveness of CD4+ Tregs together with reduced CD39 expression probably reflecting inflammatory activity of the disease.

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Section: Resultsmentioning

confidence: 99%

STAT activation in regulatory CD4⁺ T cells of patients with primary sclerosing cholangitis

Dold,

Kalthoff,

Frank

et al. 2024

Immunity Inflam & Disease

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“…Also, while we could determine sex differences in our human studies, we could not specifically measure the role of androgen signaling the human studies. Future studies using patients undergoing gender affirming care (Robinson et al, 2022) or patients with androgen insensitivity syndrome could provide this information. Additionally, all human samples were limited in that they were not timed for menstruation cycles and all medications may not have been captured at the time of death or blood draw.…”

Section: Limitations Of the Studymentioning

confidence: 99%

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Chowdhury¹,

Cephus²,

Madden³

et al. 2023

Preprint

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Females have increased prevalence of many Th17-mediated diseases. While androgen signaling decreases Th17-mediated inflammation, the mechanisms are not fully understood. Th17 cells rely on glutaminolysis; however, it remains unclear whether androgen receptor (AR) signaling in males modifies glutamine metabolism to suppress Th17-mediated inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis. Using allergen-induced airway inflammation models, we determined females, but not males, had a critical reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake by reducing expression of glutamine transporters. These findings were confirmed in circulating human Th17 cells with minimal reliance on glutamine uptake in male compared to female Th17 cells. We found that AR signaling attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for design and implementation of Th17 or glutaminolysis targeted therapeutics.

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“…Regulatory protein forkhead box P3 (FoxP3) expression has been shown to be higher in males due to parental imprinting effects, with less methylation on the maternal X allele, which is expressed exclusively in males ( 106 ). Additionally, a recent study has demonstrated that Treg frequencies are one of the top features of immune cell profiling that differentiate young post-pubertal men from women, and that male Tregs have higher suppressive capabilities due to increased phosphoinositide 3-kinases (PI3K) signaling ( 107 ). The autoimmune regulator (AIRE) gene, which is critical for Treg development, is downregulated by estrogen and progesterone and upregulated by testosterone, thereby resulting in increased thymic expression of AIRE in males compared to females ( 108 ).…”

Section: Sex Bias In T Cellsmentioning

confidence: 99%

“…Kdm6a is a histone demethylase on the X chromosome that regulates transcription of numerous genes. It has been identified as one of the top differentially expressed genes on CD4 T cells between males and females, with higher expression in females due to escape from XCI ( 107 , 188 ). Mice lacking Kdm6a in CD4 T cells have been shown to display a downregulation of neuroinflammation, TLR signaling and IL-17 signaling genes, and are protected from EAE ( 188 ), suggesting that this is an important mechanism to explain the female sex bias in MS.…”

Section: Sex Bias In Lymphocytes In Autoimmune Diseasesmentioning

confidence: 99%

Sex bias in lymphocytes: Implications for autoimmune diseases

Dodd

Menon

2022

Front. Immunol.

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Autoimmune diseases are characterized by a significant sex dimorphism, with women showing increased susceptibility to disease. This is, at least in part, due to sex-dependent differences in the immune system that are influenced by the complex interplay between sex hormones and sex chromosomes, with contribution from sociological factors, diet and gut microbiota. Sex differences are evident in the number and function of lymphocyte populations. Women mount a stronger pro-inflammatory response than males, with increased lymphocyte proliferation, activation and pro-inflammatory cytokine production, whereas men display expanded regulatory cell subsets. Ageing alters the immune landscape of men and women in differing ways, resulting in changes in autoimmune disease susceptibility. Here we review the current literature on sex differences in lymphocyte function, the factors that influence this, and the implications for autoimmune disease. We propose that improved understanding of sex bias in lymphocyte function can provide sex-specific tailoring of treatment strategies for better management of autoimmune diseases.

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Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study

Cited by 23 publications

References 34 publications

STAT activation in regulatory CD4⁺ T cells of patients with primary sclerosing cholangitis

STAT activation in regulatory CD4⁺ T cells of patients with primary sclerosing cholangitis

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Sex bias in lymphocytes: Implications for autoimmune diseases

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Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study

Cited by 23 publications

References 34 publications

STAT activation in regulatory CD4+ T cells of patients with primary sclerosing cholangitis

STAT activation in regulatory CD4+ T cells of patients with primary sclerosing cholangitis

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Sex bias in lymphocytes: Implications for autoimmune diseases

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Product

Resources

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STAT activation in regulatory CD4⁺ T cells of patients with primary sclerosing cholangitis

STAT activation in regulatory CD4⁺ T cells of patients with primary sclerosing cholangitis