bims-simsho 2025-07-27 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–07–27
fourteen papers selected by
Chun-Chi Chang, Lunds universitet

Decoding sex differences in human immunity through systems immunology.
Pregnancy and lactation induce distinct immune responses to COVID-19 booster vaccination and SARS-CoV-2 breakthrough infection.
The role of dendritic cells in recurrent pregnancy loss.
Characteristics of Gut Microbiota in Patients with Polycystic Ovary Syndrome and Its Association with Metabolic Abnormalities: A Review.
POLYCYSTIC OVARY SYNDROME: ORIGINS AND IMPLICATIONS: Gestational anti-Müllerian hormone and testosterone excess combined with maternal adiposity program for polycystic ovary syndrome.
Decoding androgen excess in polycystic ovary syndrome: Roles of insulin resistance and other key intraovarian and systemic factors.
Plasma testosterone concentration is correlated with circulating immune cell abundance in transgender young people on gender-affirming hormone treatment.
Correlation between follicular fluid of 25-hydroxyvitamin D level and endocrine function, ovarian function and insulin resistance in women with polycystic ovary syndrome.
Enrichment of decidual CD11c + CD8 + T cells with altered immune function in early pregnancy loss.
Self-Antigens Select B Cells: A New Perspective on B Cell Selection and Function.
Central memory T cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ T cell pools across the human lifespan.
The correlations between serum bone biomarkers and those related to metabolic and hormonal profile, low-grade inflammation and redox balance, in lean and overweight PCOS adolescent girls.
The role of gut microbial metabolites in the T cell lifecycle.
Functional androgen signaling pathway potentiates maternal-fetal interactions------ implantation, placentation and early pregnancy maintenance.

Oxf Open Immunol. 2025 ;6(1): iqaf006

Decoding sex differences in human immunity through systems immunology.

Joan Escrivà-Font, Tianze Cao, Camila Rosat Consiglio.

  Immune function varies widely across humans. Biological sex is a key factor underlying human immune variability, with men presenting with more severe infections and increased cancer rates, while women exhibit higher vaccine responses and prevalence of autoimmunity. Intrinsic biological sex differences arise from varying contributions of chromosomal sex, and sex hormone sensing and downstream signaling to different cell types. This complex regulation presents a unique opportunity for the exploration of human immune sex differences using systems-level methods of investigation. Here we analyze the current literature and the applications of systems immunology in elucidating the immune sex differences in humans. We examine mechanisms of biological sex modulation of human immunity via sex chromosomes, and particularly emphasize the role of sex hormones. We then focus on how systems immunology has been advancing our understanding of how sex impacts the healthy immune system at steady state, ranging from cell composition, transcriptomics, epigenomics, metabolomics, spatial and cell-cell interactions, to plasma proteomics. We also examine systems-level applications to investigating sex differences upon immune perturbations and give an overview of key future directions for the field. Systems immunology provides a powerful framework to decode biological sex-regulated pathways in immunity, paving the way for more precise, sex-informed therapeutic interventions to address sex differences in immune-related conditions.

Keywords:  biological sex; sex differences in human immunity; sex hormones; systems immunology

DOI:  https://doi.org/10.1093/oxfimm/iqaf006
JCI Insight. 2025 Jul 22. pii: e191930. [Epub ahead of print]10(14):

Pregnancy and lactation induce distinct immune responses to COVID-19 booster vaccination and SARS-CoV-2 breakthrough infection.

Kailin Yin, Lin Li, Xiaoyu Luo, Jason Neidleman, Arianna G Cassidy, Yarden Golan, Nida Ozarslan, Christine Y Lin, Unurzul Jigmeddagva, Mikias Ilala, Megan A Chidboy, Mary Prahl, Stephanie L Gaw, Nadia R Roan.

  The widespread uptake of COVID-19 vaccines by women provided a unique opportunity to study the effects of pregnancy and lactation on immune responses to vaccination. Leveraging a cohort with well-defined SARS-CoV-2 exposure history, we found that the magnitude of humoral and cellular immune responses to vaccine-delivered SARS-CoV-2 spike was not affected by pregnancy or lactation status. However, vaccination during pregnancy elicited more stem-like SARS-CoV-2-specific CD4+ T cells. Moreover, breakthrough infection promoted spike-specific IgG in pregnant individuals in contrast with IgA in those lactating, suggesting that the pregnancy-to-lactation transition favors mucosal antibody responses. Breakthrough infection also reduced peripheral cytolytic SARS-CoV-2-specific CD8+ T cell frequencies during lactation but not pregnancy, which may reflect trafficking of the cells to mammary glands. Our study also uncovered an impact of pregnancy and lactation on global T cell phenotypes. In particular, lactating individuals preferentially exhibited a state of diminished T cell activation. Furthermore, breakthrough infection during pregnancy, but not lactation, diminished frequencies of activated CD8+ T cells, tissue-homing CD8+ T cells, and γδ T cells. Our findings support the notion that immunity during pregnancy and lactation adapts to benefit the fetus or breastfed infant, with implications for eliciting effective long-term immunity for these uniquely vulnerable groups.

Keywords:  Adaptive immunity; Immunology; Reproductive biology; T cells

DOI:  https://doi.org/10.1172/jci.insight.191930
Immunol Res. 2025 Jul 21. 73(1): 108

The role of dendritic cells in recurrent pregnancy loss.

Xingxing Yuan, Chaofan Li, Liuxin Yang, Xiaoyu Zhang, Xiaoling Feng.

  Recurrent pregnancy loss (RPL), defined as ≥ 2 consecutive losses, remains a significant clinical challenge with complex immunological underpinnings. While immune dysfunction underpins RPL, dendritic cells (DCs) emerge as central regulators of maternal-fetal tolerance. This review comprehensively explores the multifaceted roles of DC subsets at the maternal-fetal interface, including their contribution to immune tolerance, angiogenesis, placental development, and bidirectional interactions with trophoblasts and natural killer (NK) cells. We detail specific DC alterations in RPL, encompassing phenotypic shifts, functional defects, and disrupted DC-NK cell crosstalk, linking these changes to pregnancy loss risk. Emerging evidence highlights therapeutic strategies targeting DCs, such as tolerogenic DC vaccines and interventions modulating trophoblast MHC antigen presentation, alongside established immunomodulation, to restore immune balance. Underlying mechanisms like systemic inflammation impacting endometrial DCs are also discussed. By synthesizing current literature and controversies, this review elucidates the critical, yet complex, role of DC heterogeneity and function in RPL pathogenesis and discusses innovative interventions aimed at improving pregnancy outcomes.

Keywords:  Dendritic cells; Immune tolerance; Natural killer cells; Recurrent pregnancy loss; Therapeutic strategies

DOI:  https://doi.org/10.1007/s12026-025-09664-z
Int J Womens Health. 2025 ;17 2165-2174

Characteristics of Gut Microbiota in Patients with Polycystic Ovary Syndrome and Its Association with Metabolic Abnormalities: A Review.

Shuang Liu, Linqi Cheng, Sen Li.

  Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder that has garnered attention in recent years for its intricate relationship with gut microbiota, which plays a significant role in the metabolic abnormalities associated with this condition. This review focuses on the characteristics of gut microbiota in polycystic ovary syndrome (PCOS). By analyzing current literature, we will focus on the alterations in gut microbiota composition, influential factors, and the pathophysiological mechanisms linking gut microbiota and PCOS, diagnostic approaches, therapeutic strategies, as well as controversies and future directions in this field are discussed. Understanding these relationships may provide insights into the disease mechanism and highlight novel treatment strategies for managing PCOS.

Keywords:  endocrine disorders; gut microbiota; metabolic abnormalities; microbiome; polycystic ovary syndrome

DOI:  https://doi.org/10.2147/IJWH.S522708
Reproduction. 2025 Aug 01. pii: e250120. [Epub ahead of print]170(2):

POLYCYSTIC OVARY SYNDROME: ORIGINS AND IMPLICATIONS: Gestational anti-Müllerian hormone and testosterone excess combined with maternal adiposity program for polycystic ovary syndrome.

David H Abbott, Jon E Levine, Phillip A Dumesic, Vasantha Padmanabhan, Daniel A Dumesic.

   In brief: A 'two hit' developmental origin involving testosterone and anti-Müllerian hormone is proposed to initiate PCOS pathogenesis during gestation. Epigenetic mechanisms amplify genetically heritable traits, while accompanying metabolic perturbations, including gestational hyperglycemia, hypertension and maternal obesity, exaggerate PCOS expression.
Abstract: Pre- or perinatal excess of anti-Müllerian hormone (AMH) or testosterone faithfully reproduce many polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in animal models. Epigenetic transgenerational transmission of such developmental programming has been repeatedly demonstrated in mice and is likely to exist in nonhuman primates. In humans, hyperandrogenic PCOS is reliably heritable and repeatedly associated with >20 PCOS risk genes and altered epigenetic signatures. Infant daughters of women with PCOS exhibit traits consistent with a hyperandrogenic fetal environment that is accompanied by precocious onset of AMH hypersecretion. Elevated AMH levels, likely of ovarian origin, persist from birth through adolescence in daughters of women with PCOS, and in adult women with PCOS, and associate with extending the reproductive years and delaying peri-menopause. Evidence is accumulating for fetal extra-ovarian production and action of AMH in various tissues: the brain, for survival of GnRH neurons migrating from the embryonic nose to the hypothalamus; the pituitary, for gonadotrope development; and the placenta, for optimal fetal support. In addition, PCOS risk genes, including those regulating androgen biosynthesis, are being identified in many families with PCOS, bestowing the potential for intrinsic androgen excess in the fetal ovary, adrenal, brain, abdominal adipose and pilosebaceous glands. A 'two hit' developmental origin may therefore promote PCOS pathogenesis during gestation when epigenetic mechanisms amplify genetically heritable traits, while accompanying metabolic perturbations, including gestational hyperglycemia, hypertension and maternal obesity, may exaggerate the phenotypic expression of PCOS.

Keywords:  animal models; developmental programming; nonhuman primate; rodents; sheep

DOI:  https://doi.org/10.1530/REP-25-0120
World J Diabetes. 2025 Jul 15. 16(7): 108789

Decoding androgen excess in polycystic ovary syndrome: Roles of insulin resistance and other key intraovarian and systemic factors.

Neervana Rambaran, Md Shahidul Islam.

  Recent studies have potentiated the essential role of androgens in normal folliculogenesis and, therefore, female fertility. Contrastingly, excess androgen levels, i.e., hyperandrogenism (HA), a hallmark characteristic of polycystic ovary syndrome, overrides the delicate balance of folliculogenesis, leading to follicular arrest and ovulatory issues. Insulin resistance (IR) has a profound effect on elevating androgen secretion and is considered one of the primary factors driving both ovarian androgen production and metabolic dysfunction in polycystic ovary syndrome. Together with IR, disruptions in key intraovarian and systemic factors, including activin, inhibin, follistatin, anti-Mullerian hormone, bone morphogenetic proteins, growth differentiation factor-9 and Kit ligand, as well as dysregulation in both the insulin and the transforming growth factor-β superfamily signaling pathway, contribute to follicular arrest, elevated androgen levels and metabolic dysfunction, exacerbating HA. Additionally, suppression of sex hormone-binding globulin, disrupted adipose-neuroendocrine signaling and altered microRNA expression heighten HA, with IR serving as the fundamental contributor. Emerging evidence implicates impaired atresia together with non-apoptotic cell death, such as ferroptosis and pyroptosis, which have also been associated with ovarian dysfunction. A comprehensive understanding of the most significant factors, particularly IR, which amplifies androgen production through hyperinsulinemia-mediated stimulation of theca cells, is essential for identifying targeted therapeutic strategies.

Keywords:  Folliculogenesis; Hyperandrogenism; Insulin resistance; Obesity; Ovary; Oxidative stress; Polycystic ovary syndrome

DOI:  https://doi.org/10.4239/wjd.v16.i7.108789
Front Immunol. 2025 ;16 1608543

Plasma testosterone concentration is correlated with circulating immune cell abundance in transgender young people on gender-affirming hormone treatment.

Alice A White, Thomas Pearce, Isabelle Coenen, Xander Bickendorf, Julia K Moore, Penelope Strauss, Liz A Saunders, Georgia Chaplyn, Aris Siafarikas, Ashleigh Lin, Martyn French, Christian Tjiam, Deborah Strickland, Jonatan Leffler.

  Sex hormones, such as oestrogen and testosterone, display significant immune modulatory properties. This is highly relevant for transgender (trans) people who undergo gender-affirming hormone (GAH) treatment. However, only a limited number of studies have evaluated the immunological impact of GAH treatments, and almost none have assessed the impact in trans young people. Following recruitment to the Gender and IMmunity study (GIM) (n =100), biological samples were collected from trans young people (n = 47) including: trans males (birth-registered females taking testosterone-based GAH) and trans females (birth-registered males taking oestrogen-based GAH). All trans participants had taken GAH for at least 6 months. Samples were also collected from control individuals not taking GAH (n = 53). Immune profiles were evaluated using an 18-colour flow cytometry panel. In addition, the commercially available 37-parameter MaxPar panel was used for analysis of a subset of samples (n = 36) by mass cytometry (CyTOF). Immune cell abundance was compared across experimental groups, and correlated with plasma concentrations of oestradiol and testosterone using multiple regression models. From multiple comparisons analyses grouped by birth-registered sex, several differences were detected in the trans groups compared to control groups, in particular relating to abundance of B and T cell subsets. These differences appeared to be mainly associated with levels of plasma testosterone. The most notable differences were in trans males, who had lower numbers of CD11c+ B cells and higher numbers of CD4+ regulatory T cells (Tregs) compared to control females. Using CyTOF, further analysis of B and T cells subsets revealed the frequency of naïve B cells was higher in trans males compared to control females. This also correlated with testosterone concentration in this group. Differences in the abundance of other T cell subsets were detected in both trans males and trans females, however only a decrease in CD161+ T effector memory cells in trans males, compared to control females, was associated with lower testosterone levels. This cross-sectional observational study of young trans individuals suggests that testosterone treatment may have immune modulatory effects, which should be investigated further, including functional studies. While oestrogen treatment was associated with differences in some immune cells in trans females compared with controls, these were generally not associated with plasma oestradiol levels but rather with testosterone levels. Continued immunological research of young trans individuals taking GAH treatment is crucial for positive long-term health outcomes.

Keywords:  B cells; CyTOF; GAH; T cells; flow cytometry; oestrogen; testosterone; transgender

DOI:  https://doi.org/10.3389/fimmu.2025.1608543
J Physiol Pharmacol. 2025 Jun;76(3):

Correlation between follicular fluid of 25-hydroxyvitamin D level and endocrine function, ovarian function and insulin resistance in women with polycystic ovary syndrome.

Y Fu, Y H Wang, L Wang, M R Huang.

This study was designed to reveal the profound association between follicular fluid vitamin D (25(OH)D) levels and the health status of women with polycystic ovary syndrome (PCOS), with the aim of laying a solid scientific foundation for the development of more precise treatment strategies for PCOS. By exploring the correlation between follicular 25(OH)D level and endocrine function, ovarian function and insulin resistance in women with PCOS, it is hoped that the potential value of this level in clinical practice can be realized. From June 2021 to March 2024, 153 women with infertility mainly due to PCOS were selected. According to the Rotterdam criteria, they were divided into phenotypes A-D, with 72 cases (47.06%), 36 cases (23.53%), 18 cases (11.76%), and 27 cases (17.65%), respectively. Forty-six healthy controls with gender and age matching were included. Endocrine function was evaluated by measuring follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and dehydroepiandrosterone sulfate. Ovarian function (ovarian volume and number of follicles) and insulin resistance index (HOMA-IR) were also assessed. PCOS patients with different phenotypes were divided into vitamin D deficiency (VDD) group (<20 ng/mL) and non-VDD group (≥20 ng/mL) according to 25(OH)D levels. The correlation between follicular fluid 25(OH)D and differential clinical features was evaluated. We found that 25(OH)D in follicular fluid of PCOS women was lower than that of controls (P<0.001). Phenotype A and B had higher LH and LH/FSH than phenotype D (P<0.05) and were hyperandrogenic, whereas phenotype D had normal or low androgens and no hyperandrogenic symptoms (P<0.05). In terms of ovarian function, PCOS women with phenotypes A, C, and D had large ovarian volumes, with more follicular fluid in A and C than in B (P<0.05). There were no significant differences in FBG, HOMA-IR, insulin sensitivity and follicular fluid 25-(OH)D among the four groups (P>0.05). In the phenotype A and B cohorts, the LH/FSH ratio, ovarian volume, and HOMA-IR of the VDD group were higher than those of the non-VDD group. There was a weak and negative correlation between follicular fluid 25(OH)D and LH/FSH levels and HOMA-IR, and a moderate correlation with ovarian volume. To sum up: PCOS women have lower follicular fluid 25(OH)D. When VDD is present, patients with phenotype A and B have higher levels of insulin resistance characteristics. Although follicular fluid 25-(OH)D does not show statistically significant differences across the different PCOS phenotypic cohorts, specific phenotypes A and B exhibit more pronounced insulin resistance profiles in those individuals with VDD.

DOI: https://doi.org/10.26402/jpp.2025.3.07
Nat Commun. 2025 Jul 21. 16(1): 6678

Enrichment of decidual CD11c + CD8 + T cells with altered immune function in early pregnancy loss.

Ling Guo, Anliang Guo, Yaqiu Guo, Shuwen Han, Cameron Klein, Zi-Jiang Chen, Junhao Yan, Yan Li.

Early pregnancy loss (EPL) is closely associated with imbalances in the maternal-foetal immune microenvironment. Here we identify CD11c + CD8 + T cells, an unconventional cytotoxic T cell subset, as significantly enriched and activated in EPL cases. These cells contribute to immune dysregulation and inhibit trophoblast invasion through secreting granzyme B, perforin, CD107a, TNF-α, and IFN-γ. Furthermore, we present an effective early prediction model for EPL, based on cytokine and cytotoxic molecule profiles of CD11c + CD8 + T cells in maternal serum, collected 12-16 days post-embryo transfer. Functional assays reveal that IFN-γ triggers trophoblast pyroptosis via the NLRP3/Caspase-1/GSDMD pathway, impairing trophoblast invasion. In vivo validation using abortion-prone mice and an anti-4-1BB antibody-induced model of CD11c + CD8 + T cell activation confirms increased embryo resorption and reduced trophoblast infiltration. These findings highlight the role of dysregulated CD11c + CD8 + T cells at the maternal-foetal interface in EPL, and suggest their potential as biomarkers and therapeutic targets for EPL-management.

DOI: https://doi.org/10.1038/s41467-025-61992-8
Eur J Immunol. 2025 Jul;55(7): e51720

Self-Antigens Select B Cells: A New Perspective on B Cell Selection and Function.

Mike Aoun, Rikard Holmdahl.

  The adaptive immune system is shaped by self-recognition, creating a paradox where autoreactivity is essential for immune regulation, yet implicated in autoimmune diseases. Traditionally, B cell selection in the bone marrow (BM) has been viewed through the lens of negative selection, eliminating potentially harmful clones. Emerging evidence challenges this perspective, revealing a subset of B suppressor cells (Bsup) that actively regulate immune homeostasis. Unlike conventional negative selection, C1-specific Bsup cells, which recognize collagen type II (Col2), engage Col2-specific regulatory T cells (Tregs) to suppress inflammation in healthy individuals. This suggests that Bsup play a role in both peripheral and central tolerance, akin to Tregs. However, the molecular mechanisms governing Bsup selection, differentiation, and function remain unknown. Understanding how Bsup distinguish homeostatic from pathogenic autoreactivity could transform autoimmune disease treatment, shifting the focus from eliminating autoreactive B cells to harnessing their regulatory potential for precision immunotherapy.

Keywords:  B cell development; autoimmunity; immune regulation; inflammation; self/non‐self discrimination

DOI:  https://doi.org/10.1002/eji.202451720
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2501167122

Central memory T cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ T cell pools across the human lifespan.

Tejas Menon, Hayley A McQuilten, Jerome Samir, Thi H O Nguyen, Ratana Lim, Jasveen Kaur, Simone Rizzetto, Auda Eltahla, Paul G Thomas, Martha Lappas, Jamie Rossjohn, Stephanie Gras, Jane Crowe, Katie L Flanagan, Fabio Luciani, Peter C Doherty, Carolien E van de Sandt, Katherine Kedzierska.

  Central memory CD8+ T cells (Tcm) represent the prominent memory T cell subset in human blood, yet the persistence of T cell receptor (TCR) clonotypic and transcriptional features of epitope-specific Tcm pools across the human lifespan remains unknown. We analyzed Tcm CD8+ T cells specific for HLA-A*02:01-M158-66 (A2/M158; a prominent influenza epitope) in newborns, children, adults, and older adults directly ex vivo. Our data provide evidence that epitope-specific Tcm CD8+ pools dominate influenza-specific memory A2/M158+CD8+ T cell responses from the early childhood until old age. Tcm gene signatures were largely maintained across the age groups, although self-renewal genes defined Tcm pools in children, while older adult Tcm A2/M158+CD8+ T cells displayed detoxication and stress profiles. TCRαβ diversity within Tcm A2/M158+CD8+ T cell pools was greater in children and older adults, when compared to adults. The key public-associated TCRαβ clonotypes largely persisted across the human lifespan, although their highest frequency was detected in adults, reflecting lower TCRαβ diversity in this group. Older adults displayed increased TCRαβ heterogeneity, underpinned by large TCRαβ clonotype expansions of private TCRαβ clonotypes. Our study highlights the importance of largely preserved virus-specific Tcm pools across the human lifespan and advocates for boosting persistent TCRαβ clonotypes within this key peripheral blood subset.

Keywords:  T cell receptors; central memory; human lifespan; influenza-specific T cells; memory T cells

DOI:  https://doi.org/10.1073/pnas.2501167122
Front Nutr. 2025 ;12 1477992

The correlations between serum bone biomarkers and those related to metabolic and hormonal profile, low-grade inflammation and redox balance, in lean and overweight PCOS adolescent girls.

Małgorzata Mizgier, Veronica Sansoni, Barbara Więckowska, Grażyna Jarząbek-Bielecka, Dorota Formanowicz, Witold Kędzia, Giuseppe Banfi, Giovanni Lombardi.

   Introduction: It has been proven that polycystic ovary syndrome (PCOS) is associated with reduced bone mineral density (BMD) and impaired bone metabolism. However, to the best of our knowledge, neither the relationship between indices of bone turnover in adolescent girls was examined, nor were lean and overweight PCOS young females compared in this regard, which were the aims of our study.
Methods: Thirty-nine PCOS subjects, aged 14-18 years, were assigned to one of the two groups: Ov/Ob (overweight/obese group, n = 14) and lean (non-overweight/non-obese group, n = 25). Fasting blood samples were collected to assess bone turnover, inflammation, oxidative stress, and hormonal markers. Basic anthropometric and biochemical data were also obtained.
Results: In Ov/Ob young females, concentrations of bone turnover markers, GlaOC, GluOC, and CTX-I (selective bone resorption marker), were lower than in lean PCOSs. However, this difference was statistically significant only for GlaOC. The serum activity of bone alkaline phosphatase (BAP), a bone formation index, tended to be higher in the Ov/Ob than in lean PCOS patients, although not significantly. Additionally, we observed an inverse association between low-grade inflammation, oxidative stress, androgen levels (total testosterone and/or DHEA-S), and BAP and/or GlaOC in both lean and Ov/Ob groups, together with a positive association between Total Antioxidant Capacity (TAC) and BAP. Moreover, fasting glucose, insulin, and HOMA-IR positively correlated with GluOC and BAP in lean girls.
Discussion: Our outcomes suggest a potential negative interaction between bone markers and immune-hormonal abnormalities featuring lean and Ov/Ob adolescent PCOS girls. Moreover, these findings suggest a positive interaction between bone metabolism and total antioxidant capacity, and insulin and glucose management exists in the body. Although these findings require further investigation, all possible preventive measures should be taken to lower inflammation, oxidative stress, and androgen levels, also keeping bone well-being/homeostasis in mind.

Keywords:  adolescent girls; bone health; obesity; overweight; polycystic ovary syndrome

DOI:  https://doi.org/10.3389/fnut.2025.1477992
Nat Immunol. 2025 Jul 21.

The role of gut microbial metabolites in the T cell lifecycle.

Melissa Tran, Jun R Huh, A Sloan Devlin.

T cells, a cornerstone of the adaptive immune system, have pivotal roles at the host-microorganism interface. The gut microbiome profoundly influences T cell biology by producing a diverse repertoire of small molecules that are sensed by host cells. These microbial metabolites regulate all aspects of the T cell lifecycle, from cell development to differentiation and activation to exhaustion. Recent studies have uncovered microbially derived molecules, including short-chain fatty acids, secondary bile acids and tryptophan metabolites, as potent regulators of T cell function. However, the full scope of microbial metabolite-T cell interactions remains largely unexplored. This Review presents a mechanistic framework linking gut microbial metabolites to discrete stages of T cell fate and function. Expanding our understanding of these intricate host-microbiome interactions will reveal new aspects of immune regulation and inspire microbiome-guided therapeutic strategies for infections, autoimmune diseases and cancer immunotherapy.

DOI: https://doi.org/10.1038/s41590-025-02227-2
Placenta. 2025 Jul 14. pii: S0143-4004(25)00305-4. [Epub ahead of print]

Functional androgen signaling pathway potentiates maternal-fetal interactions------ implantation, placentation and early pregnancy maintenance.

Yang Zhao, Jiawen Xu, Caixia Liu, Jingbo Chen, Min Deng, Qi Fan, Xiaomiao Zhao.

  A growing body of evidence demonstrates that androgens play crucial roles in female reproductive physiology. Androgen receptor (AR) expression appears at all levels of the hypothalamic-pituitary-gonadal axis and other female reproductive organ or tissue such as uterus, placenta and immune system. Via AR-mediated mechanisms, androgens regulate key reproductive processes including follicular development, embryo implantation, placental formation, and pregnancy maintenance. AR knockout models suffer from considerable reproductive defects characterized by defective follicular development, reduced ovulation, decreased fertility, even premature ovarian failure. Clinically, low maternal serum testosterone correlates with diminished ovarian reserve and adverse pregnancy outcomes. These findings establish that a critical threshold of androgen is essential for successful pregnancy. While androgen excess has long been associated with follicular dysfunction and endometrial abnormalities leading to infertility and miscarriage, emerging evidence indicates that insufficient androgen similarly compromise female reproductive function. This review synthesizes fundamental discoveries and clinical evidence elucidating androgen's multifaceted effects on female reproduction. Collectively, we underscore the physiological significance of optimal androgen signaling and the pathological consequences from androgen deficiency across reproductive process.

Keywords:  Androgen; Embryo; Follicle; Placenta; Pregnancy

DOI:  https://doi.org/10.1016/j.placenta.2025.07.073