Flip a coin: cell senescence at the maternal-fetal interface†.

During pregnancy, cell senescence at the maternal-fetal interface is required for maternal well-being, placental development, and fetal growth. However, recent reports have shown that aberrant cell senescence is associated with multiple pregnancy-associated abnormalities, such as preeclampsia, fetal growth restrictions, recurrent pregnancy loss, and preterm birth. Therefore, the role and impact of cell senescence during pregnancy requires further comprehension. In this review, we discuss the principal role of cell senescence at the maternal-fetal interface, emphasizing its "bright side" during decidualization, placentation, and parturition. In addition, we highlight the impact of its deregulation and how this "dark side" promotes pregnancy-associated abnormalities. Furthermore, we discuss novel and less invasive therapeutic practices associated with the modulation of cell senescence during pregnancy.

IL-27/Blimp-1 axis regulates the differentiation and function of Tim-3+ Tregs during early pregnancy.

Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL.

Impaired immune response against SARS-CoV-2 infection is the major factor indirectly altering reproductive function in COVID-19 patients: a narrative review.

Coronavirus disease 2019 (COVID-19) is an infectious disease affecting multiple systems and organs, including the reproductive system. SARS-CoV-2, the virus that causes COVID-19, can damage reproductive organs through direct (angiotensin converting enzyme-2, ACE-2) and indirect mechanisms. The immune system plays an essential role in the homeostasis and function of the male and female reproductive systems. Therefore, an altered immune response related to infectious and inflammatory diseases can affect reproductive function and fertility in both males and females. This narrative review discussed the dysregulation of innate and adaptive systems induced by SARS-CoV-2 infection. We reviewed the evidence showing that this altered immune response in COVID-19 patients is the major indirect mechanism leading to adverse reproduction outcomes in these patients. We summarized studies reporting the long-term effect of SARS-CoV-2 infection on women's reproductive function and proposed the chronic inflammation and chronic autoimmunity characterizing long COVID as potential underlying mechanisms. Further studies are needed to clarify the role of autoimmunity and chronic inflammation (long COVID) in altered female reproduction function in COVID-19.

HLA-DR+ CD45RA- Tregs and CD28- Treg-like cells: Potential immunologic biomarkers for reproductive aging.

PROBLEM: This study aimed to identify subsets of regulatory T cells (Tregs) associated with ovarian aging and determine whether they can be used as markers of reproductive aging. METHOD: This prospective cohort study was conducted among women of reproductive age. Basic physiological characteristics, reproductive hormones, Treg cell subsets, and correlations between these parameters were assessed. The POSEIDON criteria was used to identify women with low reproductive potential. RESULTS: The percentages of HLA-DR+ CD45RA- Tregs and CD28- Treg-like cells significantly increased with age. Women between 40 and 49 years had significantly higher percentages of HLA-DR+ CD45RA- Tregs and CD28- Treg-like cells than those at 20-29, 30-34, and 35-39 years old. Age positively correlated with FSH levels and the percentages of HLA-DR+ CD45RA- Tregs and CD28- Treg-like cells, but inversely correlated with antral follicle count (AFC) and AMH levels. Interestingly, a positive correlation was found between the percentages of HLA-DR+ CD45RA- Tregs and FSH levels, whereas an inverse correlation was found between those of HLA-DR+ CD45RA- Tregs and AFC or AMH levels. Furthermore, a significant positive correlation was observed between the percentages of CD28- Treg-like cells and AFC. Based on POSEIDON criteria, women with the percentages of HLA-DR+ CD45RA- Tregs and CD28- Treg-like cells above reference value ranges were assigned to the low prognosis groups. CONCLUSION: These findings suggest that HLA-DR+ CD45RA- Tregs and CD28- Treg-like cells can be used as immunologic markers of reproductive aging, which helps clinicians identify women with low reproductive potential and establish individualized therapeutic strategies.