Special collection on immune regulation and inflammatory mechanisms in reproductive health and disease.

Reproduction is far more than a hormonal enterprise: it is orchestrated by a dynamic and highly integrated dialogue among endocrine, neuronal, auto-/paracrine, and immune signals. Beyond its classical role in host defence, the immune system provides essential cues that sustain reproductive function across the lifespan – from gametogenesis and fertilization to implantation and parturition. In both sexes, fertility depends on a delicate tripartite balance: vigilant protection against pathogens, robust immune tolerance towards antigenically distinct germ cells and, ultimately, the semi-allogeneic embryo, and precisely controlled inflammatory processes that enable tissue remodelling and early embryonic events. vigilant protection against pathogens, robust immune tolerance towards antigenically distinct germ cells and, ultimately, the semi-allogeneic embryo, and precisely controlled inflammatory processes that enable tissue remodelling and early embryonic events. Immune–reproductive crosstalk extends systemically through the bidirectional communication of the immune system with the hypothalamic–pituitary–gonadal axis, an interaction that represents a key mechanism mediating reproductive–immune trade-offs. Disruption of this intricate immune balance both locally and systemically, through infection, dysregulated immunity, or chronic inflammation, can drive infertility, reproductive disorders (e.g. endometriosis, polycystic ovary syndrome, and epididymo-orchitis), and adverse pregnancy outcomes. This Reproduction & Fertility special collection brings together contributions from leading experts in the field, examining and updating our knowledge about the complex interplay between the immune system and reproductive health. Yet, as an online, open-access series published in Reproduction & Fertility , it remains an evolving forum – welcoming further perspectives that can deepen and enrich the ongoing conversation on reproductive immunology.

The female reproductive system faces an equally complex immunological challenge, requiring continuous balance between antimicrobial defence and tolerance to allogeneic spermatozoa, implantation of a semi-allogeneic embryo, and support of fetal development. These demands fluctuate across the menstrual cycle and pregnancy, making immune cells integral regulators of these dynamically shifting immune environments. Region-specific epithelial barriers in the female reproductive tract play a central role in this balance. The cervix functions as a physical and immunological gatekeeper, producing mucus enriched with antimicrobial peptides, immunoglobulins, and glycans that restrict pathogens while permitting sperm passage during the peri-ovulatory period ( Wira et al. 2015 ). In the uterus and fallopian tubes, epithelial cells modulate leucocyte recruitment in a hormone-dependent manner, coordinating mucosal defence and embryo protection. Ovulation itself exemplifies the integration of immune and reproductive processes, resembling a controlled inflammatory event. Macrophages, neutrophils, and mast cells orchestrate follicular rupture through cytokine signalling, proteolytic activity, and vascular remodelling ( Dai et al. 2023 ). Across the menstrual cycle, fluctuating oestrogen and progesterone dynamically shape leucocyte abundance and phenotype of uterine immune populations. During the progesterone-dominant secretory phase, these immune populations adopt tissue-remodelling and pro-implantation phenotypes that prepare the endometrium for embryo implantation. In the absence of pregnancy, progesterone withdrawal triggers a rapid shift in immune function, driving a coordinated inflammatory cascade that underpins menstrual breakdown, repair, and regeneration. In this context, in this special collection, a review by Jacqueline Maybin and colleagues provides a timely and comprehensive synthesis of the mechanisms linking menstrual inflammation to both normal and pathological uterine bleeding. Early pregnancy represents the most delicate phase of this immune coordination. Successful implantation requires a precisely timed sequence of immune events at the fetal–maternal interface. A transient pro-inflammatory phase supports decidualization, trophoblast invasion, and vascular adaptation, followed by a rapid transition to a tolerogenic state. Decidual natural killer (NK) cells adopt a low-cytotoxic, pro-angiogenic phenotype; Treg cells expand to suppress maternal immune responses against fetal antigens ( Robertson et al. 2013 ); and decidual macrophages clear apoptotic trophoblasts to avert secondary inflammation ( Park et al. 2025 ). In the lower female reproductive tract, epithelial cells in the vagina and cervix work together with resident immune cells to maintain continuous surveillance against pathogens. However, these defences remain tightly regulated to preserve fertility. Hormonal fluctuations modulate epithelial barrier integrity and immune responsiveness, creating windows of increased susceptibility to ascending infection. When dysregulated, these mechanisms can contribute to pelvic inflammatory disease and long-term reproductive complications. In this collection, Amber Thornton and Heloisa Rutigliano examine the mechanisms that prevent the maternal immune rejection of the semi-allogeneic embryo, focusing on bovine pregnancy. Their analysis highlights conserved principles of maternal–fetal immune dialogue and illustrates how disruptions in immune tolerance can compromise pregnancy success. As reproductive success depends on precise immune timing and coordination, even subtle disruptions can have profound consequences. Immune dysregulation contributes to a spectrum of reproductive disorders ranging from implantation to pregnancy complications. In endometriosis, for example, macrophages fail to efficiently clear ectopic endometrial tissue and instead adopt pro-disease phenotypes that promote lesion persistence. In the peritoneal cavity, a paradoxical immune tolerance that supports lesion survival coexists with an inflammatory eutopic endometrium that impairs implantation. Similarly, in PCOS, systemic low-grade inflammation and altered macrophage polarization disrupt ovulation, endometrial receptivity, and metabolic homeostasis. A review by Marcelo Cavalcante and colleagues highlights how inflammatory networks contribute to PCOS pathophysiology and highlights the therapeutic potential of targeting immune dysregulation. In recurrent pregnancy loss (RPL), delayed decidual transition and immature tolerogenic uterine NK populations may compromise implantation and early placentation. Recurrent implantation failure may likewise reflect insufficient or mistimed decidual-immune activation. Beyond implantation, impaired maternal–fetal immune tolerance can contribute to complications including miscarriage, preeclampsia, fetal growth restriction, and preterm birth. In support of this paradigm, Kylie Belchamber and colleagues review the role of decidual macrophages in maintaining placental immune homeostasis through efferocytosis of apoptotic trophoblasts, a process that promotes anti-inflammatory macrophage phenotypes but appears impaired in pregnancy complications. Several studies in this collection further illustrate the impact of maternal immune health on pregnancy outcomes. Rachel West and colleagues demonstrate that placental stem cells are highly sensitive to maternal immune signals, underscoring the importance of the maternal immune environment during placental development. Complementing this work, Mancy Tong and colleagues show that viral inflammatory signals, including prior exposure to double-stranded RNA, can impair endometrial decidualization in both human cell culture and assembloid models, as well as mouse models of pregnancy, linking infection-induced inflammation to pregnancy loss and placental disease. Inflammation associated with infection also represents a major threat to fertility. Pelvic inflammatory disease and persistent sexually transmitted infections can lead to tubal scarring, obstruction, and hydrosalpinx formation. Inflammatory fluid from damaged fallopian tubes can reflux into the uterine cavity, altering the local immune environment and reducing implantation rates even during assisted reproduction. Within this context, Christopher Hill and colleagues present new insights into immune cell alterations in hydrosalpinx, providing a foundation for future mechanistic studies of tubal immune pathology. Collectively, these examples highlight how immune dysregulation, whether driven by infection, chronic inflammation, or impaired tolerance, can disrupt reproductive processes at multiple stages.

Despite growing interest in reproductive immunology, significant challenges remain in fully understanding the complex interplay between the immune and reproductive systems. Both systems are highly dynamic: immune activity and reproductive function vary across sex, age, and hormonal status and, in females, additionally fluctuate across menstrual or oestrous cycle phases, pregnancy, and menopause. These intrinsic variations are compounded by lifestyle and environmental factors (e.g. diet, metabolic health, infections or inflammation, and endocrine disruptions), which continuously modulate immune–gonadal communication in ways that remain poorly defined, making mechanistic relationships difficult to capture. Experimental models address some aspects of these complexities but remain imperfect. Mouse models have been indispensable, yet fundamental physiological differences, such as the absence of menstruation and spontaneous decidualization in females, distinct uterine NK cell behaviours, and limited genetic diversity in inbred strains, constrain their relevance for studying human implantation, menstrual inflammation, and disorders such as endometriosis. In males, core processes, such as spermatogenesis and hormonal regulation, are largely conserved, but subtle anatomical and physiological differences, including resident immune cell populations, must be considered. In vitro systems, including organoids of endometrium, trophoblast, ovary, or testis/epididymis, provide valuable experimental tools but still lack immune complexity and cannot fully replicate the spatial, mechanical, and endocrine complexity of the in vivo niche. The role of epithelial cells as immunological participants across these tissues also remains largely underexplored. Access to human reproductive tissues remains limited due to ethical and practical constraints, particularly for samples such as endometrium during specific phases of the menstrual cycle, early pregnancy tissues, or testicular and epididymal samples from healthy donors. Diagnostic challenges further complicate research in this field, as many investigations rely on invasive tissue sampling, and robust biomarkers of local immune activity remain lacking. In addition, human studies are often restricted to relatively homogeneous populations in high-income countries, despite clear evidence that environmental exposures, lifestyle factors, and health disparities shape reproductive immune responses ( Bierer et al. 2022 ). These limitations highlight important gaps in our understanding of reproductive immunology. In particular, further studies are needed to clarify the relationship between the tissue microbiome (including microbial communities in the gut and reproductive tract), dysbiosis, and fertility outcomes, as microbial populations are increasingly recognized as key regulators of local immune microenvironments relevant to reproduction. Several contributions to this collection aim to address these challenges. For example, Priscilla Day-Walsh and colleagues review microbiome-informed strategies for predicting and preventing pregnancy complications, highlighting the potential of microbial and immune signatures to improve risk prediction for outcomes such as miscarriage, stillbirth, preeclampsia, fetal growth restriction, and preterm birth. Complementing these approaches, Alex Richter and colleagues present novel insights into systemic cytokine dysregulation in RPL and explore the potential use of pro- and anti-inflammatory cytokine ratios as candidate biomarkers, illustrating how systemic immune profiling could complement tissue-based studies and support earlier detection of immune-associated RPL. Emerging multi-omics approaches, coupled with advanced microscopy and high-resolution immune profiling, offer a powerful avenue to move beyond classical descriptive studies towards mechanistic, system-level understanding. Critically, the public availability of datasets is essential to enable cross-study integration, foster reproducibility, and accelerate discovery. Resources such as ‘ShinyEpididymis’ in epididymal proteomics illustrate how interactive, web-based platforms allow researchers to explore spatial, temporal, and functional patterns across datasets, identify potential biomarkers, and share insights globally ( Trigg et al. 2026 ). Standardizing data integration and addressing current analytical challenges will be essential to fully exploit these technologies and uncover how sex-specific, tissue-specific, and environmental signals collectively shape immune–reproductive interactions.

This work was supported by the São Paulo State Research Foundation (grant number 2021/06718-7 to EJRS); National Council for Scientific and Technological Development (grant number 303616/2022-9 to EJRS); and German Research Foundation (DFG), Research Units Programme (FOR) 5644 ‘INFINITE’ (project no. 515636567 to CP).

The male reproductive tract embodies a fundamental immunological paradox: spermatozoa, which express antigens that arise during puberty – long after central immune tolerance has been established, require specialized immune environments to avoid autoimmune reactions while still responding quickly to infection and inflammation. This is particularly required within the testis and epididymis. In the testis, structural barriers, i.e. the blood–testis barrier, alongside coordinated signalling between Sertoli cells, Leydig cells, and resident immune cell populations, establish a tightly regulated immune-privileged niche. Rather than merely excluding immune activity, this environment actively promotes regulatory and anti-inflammatory pathways that support steroidogenesis, germ cell proliferation and differentiation, and tissue homeostasis. Testicular macrophages and other leucocyte subsets contribute to this balance by favouring immunosuppressive phenotypes under steady-state conditions, although many mechanisms remain incompletely defined ( Rodriguez et al. 2025 ). This special collection will include an original article by Daniela Fietz and Loveland colleagues, shedding light on how immune cells are distributed already in the fetal testis using rarely available tissue from stillborn donors. Studies like these are critically important for understanding how the delicate interplay between the immune and reproductive systems is established very early in life and for translating mechanistic insights from mouse models (e.g. Tony DeFalco and colleagues) into the human context. After being released from the immune-privileged environment of the testis, sperm are transported to the epididymis, where they undergo complex biochemical maturation required to acquire their full fertilization competence. In contrast to the testis, the epididymis constitutes a more immunoreactive mucosal tissue, and immune regulation becomes more regionally structured and adapted to the unique needs of maturing spermatozoa ( Hedger 2011 ). The epididymal epithelium forms selective barriers and secretes immunomodulatory factors that shape a distinct luminal environment for sperm maturation. Additionally, connective septal structures compartmentalize the epididymal duct into different segments, and the blood–epididymis barrier, while not as elaborate as the blood–testis barrier, tightly regulates access to the lumen. In this dynamic system, epithelial cells actively calibrate the luminal milieu in a region-specific manner ( Voisin et al. 2019 , Rodriguez et al. 2025 ). Along the epithelium, a dense network of immune cells, i.e. mononuclear phagocytes, establishes an immunological ‘bottleneck’ that promotes tolerance to sperm and restricts pathogen ascent; distally, where pathogens enter the organs, dendritic cells and lymphocytes cluster near vascular and lymphatic entry sites to form a surveillance checkpoint. Together, these multilayered structural and cellular mechanisms enable the epididymis to balance sperm maturation with immune defence. In recent years, intensive research has generated a growing number of insights into how the immune system maintains this delicate equilibrium. In this collection, Christiane Pleuger, Rukmali Wijayarathna, and colleagues assemble these puzzle pieces into a forward-looking review that weaves together recent discoveries in epithelial signalling, barrier biology, and immune cell specialization and function. By ‘stitching together’ the emerging pieces of the puzzle, they provide an integrated framework for understanding how regional immune regulation safeguards fertility while preserving host defence. When the regional immune architecture is disturbed, male fertility can decline rapidly. Infection, sterile inflammation, or altered immune–epithelial communication can disrupt barrier integrity and activate local immune cells inappropriately. The consequences include impaired spermatogenesis, altered sperm maturation, reduced sperm motility, autoimmunity against spermatozoa, and inflammatory tissue damage resulting in ductal stenosis ( Fijak et al. 2018 ). Importantly, owing to their distinct immune environments, the testis and epididymis generally respond differently to inflammatory challenges. While the immune-privileged testis may recover from transient insults, the epididymis – particularly the cauda epididymidis – tends to exhibit more sustained pro-inflammatory responses that may persist and lead to tissue damage that directly affects male fertility ( Pleuger et al. 2020 ). This intriguing regionalized immunity reflects the highly regionalized immune organization of the epididymis. Understanding these region-specific immune trajectories is essential for designing targeted immunomodulatory interventions that mitigate tissue damage and thus preserve fertility – a topic that is further outlined in the review by Pleuger, Wijayarathna, and colleagues. Ascending uropathogens and sexually transmitted infections are the most common cause of epididymo-orchitis, although viral infections and sterile inflammatory processes can likewise compromise reproductive function in a long-term fashion ( Fijak et al. 2018 ). Building on existing evidence that viral diseases, such as COVID-19, may affect male reproductive health, an original contribution by Estela Sasso-Cerri and colleagues demonstrates that SARS-CoV-2 infection in K18-hACE2 mice results in severe immunopathology within the cauda epididymidis and severely disrupts the microenvironment essential for sperm maturation and storage.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this commentary.

CP conceived the commentary. CP, EG, and EJRS equally contributed to the drafting, writing, editing, and finalization of the commentary.