T-cell immunoglobulin and mucin domain 3 (TIM-3), a well-known immune checkpoint molecule, is increasingly recognized for its regulatory functions beyond T cell exhaustion, particularly in macrophages. Recent advances have revealed the important role of this molecule in various pathological and physiological conditions. The demand for a comprehensive study of TIM-3 is increasing, particularly as a result of ongoing clinical trials targeting TIM-3 in oncology. This review is devoted to the role of TIM-3 in macrophage biology, focusing on associations between TIM-3 expression and macrophage polarization states and functional activity, as well as its involvement in the pathogenesis of different diseases and reproductive immunology. The review examines known effects and molecular mechanisms by which TIM-3 regulates macrophage functional phenotype and the contribution of TIM-3-expressing macrophages to cancer, pregnancy, inflammation, infectious and autoimmune diseases, and fibrosis. Findings highlight the controversial role of TIM-3 in the regulatory function of macrophages and suggest that TIM-3 functions differently depending on the context. The review also touches on gaps and unexplored parts of the topic. A summary of current data allows us to conclude that TIM-3 is an important modulator of macrophage functions and can be considered a potential therapeutic target in various pathological conditions.

Bibliometric analysis of Hofbauer cell research over the past two decades: Trends and perspectives.

Bushen Guchong decoction facilitates M2 polarization through JAK2/STAT3 for URSA treatment.

Preface: 13th International Workshop Reunion Island Reproductive Immunology, immunological tolerance and immunology of preeclampsia; 9-12 December 2024.

BackgroundUnexplained recurrent spontaneous abortion (URSA) poses significant clinical challenges, with immune dysregulation at the maternal–fetal interface implicated in 80% of cases. While RNA modifications like N7-methylguanosine (m7G) are emerging as key regulators of immune pathologies, their role in URSA remains unexplored.MethodsDecidual transcriptomes (GSE165004) from URSA patients and controls were analyzed to identify differentially expressed m7G regulators. Machine learning (LASSO/random forest) prioritized diagnostic biomarkers, which were validated via qRT-PCR and immunofluorescence. Differences in the immune infiltration landscape between the two groups were assessed by ssGSEA. Furthermore, Spearman correlation analysis was performed to explore associations between m7G-related biomarkers and immune infiltration characteristics. Regulatory networks (transcription factors/microRNAs) and therapeutic candidates of biomarkers were predicted using JASPAR, mirTarbase, and Coremine medical, respectively.ResultsThree key m7G regulators with diagnostic value were identified: LSM1, LARP1, and NCBP2. The nomogram constructed based on these biomarkers demonstrated excellent predictive performance in URSA. qRT-PCR and immunofluorescence confirmed that LSM1 expression was upregulated in URSA samples, while LARP1 and NCBP2 were downregulated. Furthermore, distinct patterns of immune infiltration were observed between URSA and control. Spearman analysis revealed that LSM1 was negatively correlated with Treg infiltration, whereas LARP1 and NCBP2 showed positive correlations with Treg. Besides, network analysis identified regulatory relationships between these biomarkers and 167 miRNAs (e.g., hsa-miR-27a-3p) or 18 TFs (e.g., E2F1, GATA2). Sirolimus (targeting NCBP2) and AZD4547 (targeting LSM1) were predicted to be the most promising therapeutic drugs.ConclusionsThis study establishes m7G methylation as a novel epigenetic driver of immune dysregulation in URSA. The predictive signature offers translational tool for risk stratification and targeted therapy, bridging RNA epigenetics with reproductive immunology.

A 2025-update of "historical evolution of ideas on eclampsia/preeclampsia'' (2017, workshop reunion 2016).

SUMMARYTransplantation of allogeneic organs requires lifelong immunosuppression to prevent rejection. Prior sensitization and resultant memory T cells are barriers to achieving successful transplant tolerance. In reproductive immunology by contrast, pregnancy represents a spontaneous model of tolerance where the semi-allogeneic fetus evades rejection even in multiparous or rejection-sensitized mothers. CD8+ T cell phenotypes of tolerance and rejection have been previously reported in transplant and pregnancy, but the transcriptional states of donor and fetus-specific CD4+ T cells remain poorly defined. Here, we performed Single-cell RNA-sequencing on endogenous, antigen-specific CD4+ T cells across models of allogeneic heart transplants and naïve or paternal skin-sensitized pregnancy. We identified expanded T follicular helper (Tfh) and non-follicular effectors in transplant rejection absent in tolerance. Naïve pregnancy resulted in a modest expansion of effector clusters with transcriptional quiescence that mirrored virgin mice. Successful sensitized pregnancy resulted in expanded Tfh clusters consistent with increased fetal-specific antibodies and limited non-Tfh effector responses. Most striking were the extensive changes imposed on donor-specific Foxp3pos regulatory T cells (Tregs) resulting in the co-clustering together with Foxp3neg T conventional cells (Tconvs) in transplant tolerance and the emergence of a Foxp3neg Type I Regulatory cluster observed in pregnancy of sensitized dams. Finally, we showed that these transcriptomes were relevant and enriched in human datasets of health and disease respectively. Thus, the context-dependent signatures of antigen-specific CD4+ T cells provide new insights into their divergent responses to allogeneic conflict at the intersection of transplant and reproductive immunology.

Miscarriage and preterm birth (PB) remain major challenges in obstetric care and are often associated with excessive inflammation at the feto-maternal interface. Although the role of progesterone (P4) in maintaining pregnancy is well known, its anti-inflammatory effects in immune-mediated pregnancy complications remain poorly understood. In this study, we investigated the impact of prophylactic P4 administration on miscarriage using a mouse model induced by α-galactosylceramide (αGC), a potent activator of invariant natural killer T (iNKT) cells. Prophylactic, but not therapeutic, P4 administration significantly reduced miscarriage rates. Flow cytometry analysis revealed that P4 suppressed the activity of iNKT cells and the production of inflammatory cytokines by these cells in the myometrium. Moreover, P4 reduced the immunostimulatory activity of antigen-presenting cells, particularly macrophages, by downregulating co-stimulatory molecules and interleukin (IL)-12 production. Immunohistochemistry and flow cytometry results demonstrated that the progesterone receptor (PR) was predominantly expressed on myometrial macrophages. Ex vivo experiments further confirmed that P4 directly modulates macrophage function, decreasing IL-12 and increasing IL-10 production. These findings suggest that prophylactic P4 administration mitigates immune activation at the feto-maternal interface by targeting macrophages, thereby suppressing iNKT cell-mediated inflammation and preventing miscarriage. This study highlights the importance of innate immune modulation in reproductive immunology and the potential of P4 as a prophylactic agent for preventing inflammation-associated miscarriage and PB.

Abstract Introduction Pregnancy poses an immunological paradox: the maternal immune system must tolerate a semi-allogeneic fetus while maintaining defense against infections. Rather than being an immunosuppressed state, gestation is now recognized as a dynamic, highly regulated immune condition. Content This review applies the cancer-derived immunoediting framework – elimination, equilibrium, and escape – to maternal–fetal immune tolerance. We examine how immune checkpoints, regulatory T cells, non-classical MHC molecules, and placental exosomes coordinate to create a localized tolerant environment. Integrating knowledge from oncology and reproductive immunology, this perspective provides a unifying concept for pregnancy immune regulation. Summary The immunoediting framework reinterprets obstetric disorders such as preeclampsia, recurrent pregnancy loss, and preterm birth as failures of distinct immune phases rather than isolated pathologies. This conceptual shift allows for a broader understanding of how immune balance influences implantation, placental development, and fetal growth. Outlook Adopting an immunoediting perspective highlights potential clinical advances, including immune checkpoint modulation, regulatory T-cell therapies, and exosome-based biomarkers, paving the way for innovative diagnostic and therapeutic strategies in pregnancy care.

Trained immunity in pregnancy: Impact on maternal-fetal outcomes and mechanistic insights.

Function of chemokines in embryo implantation.

Reproductive Immunology: Current Knowledge and New Perspectives

Immunological factors have gained growing recognition as key contributors to recurrent pregnancy loss (RPL) after in vitro fertilization (IVF), representing a major challenge in reproductive medicine. RPL affects approximately 1-2% of women trying to conceive naturally and up to 10-15% of those undergoing IVF, where overall success rates remain around 30-40% per cycle. An imbalance in maternal immunological tolerance toward the semi-allogeneic fetus during pregnancy may lead to miscarriage and implantation failure. IVF-related ovarian stimulation and embryo modification offer additional immunological complications that can exacerbate existing immune dysregulation. Recent advances in reproductive immunology have significantly deepened our understanding of the immune mechanisms underlying RPL following IVF, particularly highlighting the roles of regulatory T cells (T regs), natural killer cells, cytokine dysregulation, and disruptions in maternal-fetal immune tolerance. In order to better customize therapies, this evaluation incorporates recently discovered immunological biomarkers and groups patients according to unique immune profiles. Beyond conventional treatments like intralipid therapy and intravenous immunoglobulin, it also examines new immunomodulatory medications that target certain immune pathways, such as precision immunotherapies and novel cytokine modulators. We also discuss the debates over immunological diagnostics and therapies, such as intralipid therapy, intravenous immunoglobulin, corticosteroids, and anticoagulants. The heterogeneity of patient immune profiles combined with a lack of strong evidence highlights the imperative for precision medicine to improve therapeutic consistency. Novel indicators for tailored immunotherapy and emerging treatments that target particular immune pathways have encouraging opportunities to increase pregnancy success rates. Improving management approaches requires that future research prioritize large-scale clinical trials and the development of standardized immunological assessments. This review addresses the immunological factors in RPL during IVF, emphasizing underlying mechanisms, ongoing controversies, and novel therapeutic approaches to inform researchers and clinicians.

Reproductive immunology has advanced significantly, recognizing the immune system as crucial in pregnancy development and facilitating the identification of abnormalities causing recurrent reproductive failure, as well as proposing targeted treatments for these patients. This is a descriptive, observational, and retrospective study conducted at the Reproductive Immunology Unit of the Hospital Clínico San Carlos in Madrid. Clinical and analytical data were analyzed for patients diagnosed with recurrent reproductive failure between 2019 and 2023. Data on treatments received as prophylaxis for pregnancy loss and their success rates were also collected. Finally, a comparative study of the two major subgroups in the cohort was performed. A total of 277 patients were included. The most prevalent diagnosis was recurrent miscarriage (64.2%), followed by recurrent implantation failure (25.2%). Immunological and/or vascular abnormalities were detected in 88.8% of patients. The most prevalent immunological abnormality was the expansion of cytotoxic natural killer cells (49.5%), followed by HLA-C-KIR mismatch (39.1%) and the presence of antiphospholipid antibodies (38.5%). The comparative study between the recurrent miscarriage and the recurrent implantation failure subgroups revealed statistically significant differences regarding the presence of antinuclear antibodies (15.4% vs. 28.3%, p=0.03) and vitamin D deficiency (37.2 vs 60.0%, p=0.01). The most commonly used medications were low-dose acetylsalicylic acid, low-molecular-weight heparin, hydroxychloroquine, and/or prednisone, with an overall success rate of 97.3%. Neither moderate nor severe side effects were reported. Immunological studies to identify causes of recurrent reproductive failure are highly useful in cases where other etiologies have been excluded. Targeted therapies for addressing these abnormalities have demonstrated significant effectiveness.

Natural killer (NK) cell education, a dynamic and finely tuned process, is essential for calibrating decidual NK (dNK) cell responsiveness at the maternal-fetal interface. This education process, governed by distinct receptor-ligand interactions, refines dNK cell function to maintain immune tolerance while preserving responsiveness to pathological threats. Killer-cell immunoglobulin-like receptors (KIRs) interacting with human leukocyte antigen (HLA)-C dictate a balance between activation and inhibition, shaping dNK cell adaptability to maternal-fetal genetic variation. The NKG2A-HLA-E axis establishes a foundational inhibitory checkpoint, ensuring immune tolerance through metabolic and functional programming. LILRB1-HLA-G interactions promote immunomodulatory and angiogenic functions crucial for placental development, while SLAM family receptors (SFRs), including 2B4-CD48, modulate activation thresholds and restrain excessive cytotoxicity. Disruptions in these finely orchestrated pathways contribute to recurrent implantation failure, pregnancy loss, and preeclampsia. This review synthesizes the diverse mechanisms of NK cell education, highlighting how specific receptor-ligand interactions regulate dNK cell function and maternal-fetal immune adaptation. A deeper understanding of these pathways not only enhances our comprehension of reproductive immunology but also paves the way for novel therapeutic strategies targeting immune dysregulation in pregnancy-related disorders.

The testicular immune microenvironment sustains homeostasis and immune privilege. However, the presence and functional significance of B cells within this specialized niche remain poorly characterized. Furthermore, the intricate crosstalk between resident immune populations and testicular stromal cells that may orchestrate the immunological and endocrine microenvironment during sexual maturation warrants systematic investigation. To systematically delineate the immune cell atlas and developmental trajectory of testicular leukocytes before and after sexual maturation. An integrated analysis of leukocytes in post-sexual maturity (8-week-old) and pre-sexual maturity (2-week-old) mouse testes using single-cell RNA sequencing (scRNA-seq) and mass cytometry (CyTOF), was performed. Magnetic-activated cell sorting (MACS) isolated immune subsets, followed by bioinformatics interrogation of cellular heterogeneity and ligand-receptor network analysis to map intercellular communication pathways. Through scRNA-seq clustering analysis, we resolved 18 distinct leukocyte populations (11 lymphoid and seven myeloid lineages), which were further validated and expanded to 17 phenotypically discrete subsets (eight lymphoid and nine myeloid) via high-dimensional CyTOF profiling. Notably, we identified a rare but functionally significant B lymphocyte population within the testicular compartment. The myeloid compartment exhibited pronounced developmental plasticity, marked by progressive Il1b+Macrophages diminution and regulatory T cell expansion during maturation. Cell communication network analysis revealed intensified ligand-receptor cross-talk between androgen-producing Leydig cells and CD8+ T lymphocytes in post-pubertal testes, providing mechanistic insights into age-dependent immune privilege establishment. Multi-omics integration reveals dynamic immune remodeling during testicular maturation. These findings underscore the potential involvement of B cells in local immune surveillance while identifying maturation-associated signaling axes between stromal and immune cells. This comprehensive mapping of testicular leukocyte dynamics significantly advances our understanding of reproductive immunology and lays foundation for investigating immune-mediated testicular pathologies.

Abstract Female reproduction impacts whole-body physiology, ecology, and Darwinian fitness, as endocrine and physiological changes affect peripheral body systems and maternal behavior and compose the basis and constraints of reproductive success. In mammals, relative to males, females experience an even greater reproductive burden as a result of the dynamic hormonal and physiological shifts seen throughout pregnancy, lactation, and reproductive delays. The intersection between the reproductive and immune systems is particularly dynamic, as it fluctuates between cooperative interactions, such as when inflammation facilitates implantation and placentation, and opposing interactions, such as when the adaptive immune response is suppressed to avoid harm to sperm or the conceptus. These two systems share coevolved pathways and regulators that function to bring balance to maternal-offspring interactions. Maternal immune suppression throughout reproduction may exemplify potential trade-offs whereby suppression of the systemic immune system to protect the conceptus comes at a cost of maternal survival. Reciprocally, a robust immune response to protect maternal health may come at the cost of reproductive success. We outline the major cellular mechanisms of immune and reproductive interactions from copulation to parturition to help extrapolate fitness consequences. By addressing the effects of reproductive immunology on fitness, we discuss possible trade-offs that may exist, resulting from these interactions.

Abstract Study question In a population of patients with unexplained infertility with recurrent pregnancy or implantation failure, do certain KIR-HLA phenotypes or their combinations have an increased prevalence? Summary answer In this study, though individual KIR-HLA phenotypes or combinations were not significant; KIR phenotypes Bx and AA were found overrepresented in this RIF/RPL population. What is known already Killer immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA) interactions are key modulators of immune responses for implantation. Previous studies suggest that specific KIR phenotypes, particularly KIR-Bx and KIR-AA, could be associated with adverse reproductive outcomes, including recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). HLA molecules, especially HLA-C, interact with KIRs to influence natural killer cell function at the maternal-fetal interface. Despite emerging evidence linking certain KIR and HLA combinations to infertility, results remain inconsistent and further investigation is needed to clarify their role in unexplained infertility cases as demonstrated previously. Study design, size, duration This retrospective observational study reviewed patient records from January 2022 to December 2024 at a fertility clinic’s reproductive immunology unit. We analyzed 293 patients with unexplained infertility presenting as RIF or RPL. Data regarding KIR and HLA genotypes were collected along with immunological parameters. The study aimed to evaluate the frequency and distribution of individual KIR and HLA phenotypes as well as their combinations, with a specific focus on known pathologic KIR types. Participants/materials, setting, methods Participants included women with RIF or RPL referred for immunological evaluation.KIR and HLA genotyping was performed using standardized molecular techniques on peripheral blood samples. Clinical data was meticulously extracted from patient medical records. The study was conducted at a reproductive immunology at a single center fertility clinic, employing retrospective methods to assess immunogenetic profiles and prevalence of individual and combined phenotypes in cases of unexplained infertility. Main results and the role of chance In our retrospective analysis of 293 patients with unexplained RIF and RPL, we determined the frequencies of KIR and HLA phenotypes. KIR BA (37.20%, p = 0.372) emerged as the most common phenotype, followed by KIR-AA, BX, and BB. Among HLA phenotypes, C1/C2 (45.73%) was slightly more frequent than other phenotypes. The most frequently observed KIR–HLA combination was KIR-AA with HLA-C1C2, even though KIR-AA was not the most prevalent phenotype overall. Although KIR phenotypes Bx and AA, previously linked to adverse reproductive outcomes, were common individually, neither reached the majority threshold. However, when combined as a ‘pathologic KIR’ group, these phenotypes accounted for 55.3% (n = 162) of the sample. A one-sample proportions test using χ² statistic yielded a p-value=0.039, indicating a statistically significant overrepresentation of pathologic KIR. In contrast, HLA phenotypes and other KIR–HLA combinations did not significantly deviate from expected distributions. These findings suggest that specific KIR phenotypes may be associated with reproductive failure. These findings highlight the potential relevance in the pathophysiology of RIF and RPL. These significant findings support the hypothesis that certain immunogenetic factors have an important impact on fertility, particularly pathologic KIR phenotypes, emphasizing the need for further research into immunogenetic markers in infertility. Limitations, reasons for caution This study is limited by its retrospective nature and the sample size, which may not have been large enough to detect small differences in KIR or HLA-C distributions. Also, inclusion of paternal HLA-C data could offer insights into KIR-HLA interactions, improving our understanding of their role in adverse reproductive outcomes. Wider implications of the findings These findings contribute to a growing body of evidence on the immunogenetic factors influencing reproductive outcomes. Although further validation is necessary, the overrepresentation of pathologic KIR phenotypes may guide future research and therapeutic strategies in managing unexplained implantation failure and recurrent pregnancy loss, and ultimately enhance targeted personalized treatment outcomes. Trial registration number No

Recent advances in immunology have broken barriers in reproductive medicine through immune-modulating therapies that support fertility and pregnancy. Treatments such as intravenous immunoglobulin (IVIG) and intralipid infusions are increasingly offered to patients with Recurrent Implantation Failure (RIF) or Recurrent Pregnancy Loss (RPL), conditions that result in miscarriages and failed IVF treatments (Pillarysetti et al., 2023). Maternal-fetal immunology reveals a delicate interplay between immune tolerance and defense: the maternal system must accept a genetically foreign fetus while preserving immunological protection. Disruptions in this balance are implicated in implantation disorders and pregnancy failure. As a result, immune-based therapies have emerged as promising interventions, though they raise ethical concerns about informed consent, medical paternalism, patient safety, and the tension between autonomy and provider responsibility. Despite their potential, patient decision-making may be undermined by misinformation and the emotional vulnerability of grieving parents. Consequently, reproductive immunotherapy occupies an ethically fraught space demanding clearer regulatory oversight and attention to moral considerations. Upholding reproductive autonomy requires more than offering treatment; it necessitates transparent, evidence-based, and ethically sound practices. This thesis examines ethical and informed consent challenges in reproductive immunology, focusing on gaps between patient understanding and therapeutic risks, conflicts between maternal and fetal interests, and the commercialization of these therapies in private fertility clinics. It draws on bioethical principles and alternative frameworks such as relational autonomy and the ethics of care.

Various immunomodulatory treatments have been applied to women with recurrent pregnancy losses since a significant proportion of them have cellular and autoimmune abnormalities. However, immunomodulatory treatments are often considered controversial for their efficacies. Often, they are provided to unselected patients without investigating potential etiologies by healthcare providers without appropriate reproductive immunology training and qualifications. To eliminate these concerns, the American Society for Reproductive Immunology (ASRI) established the Clinical Reproductive Immunology Fellowship and has been certifying reproductive immunologists. The approach to RPL from a reproductive immunology perspective requires a detailed understanding of underlying immunopathology, advanced knowledge of clinical and basic science and translational research, and the capability to evaluate the available evidence. The immunotherapy guideline development group, composed of clinical reproductive immunology fellows, ASRI, reviewed the currently available data and developed the clinical guidelines for immunotherapy.