Regulatory T-cells in Reproductive Medicine: Implications for Endometriosis-Associated Infertility and Implantation Immunity

The 2025 Nobel Prize in Physiology or Medicine recognized the foundational significance of identifying CD4⁺CD25⁺FOXP3⁺ regulatory T-cells and elucidating the mechanisms of immune tolerance, reshaping our understanding of self‑tolerance, autoimmunity, and tumor immunity [ 1 ]. The accompanying scientific background systematically positions the principle that Tregs preserve tissue homeostasis by controlling self‑reactive responses [ 1 ], and this principle directly extends to reproductive phenomena that require maternal-fetal immune tolerance [ 1 - 3 ].

Physiological roles of Tregs in reproductive immunology Because the mother must immunologically accept a fetus bearing semiallogeneic antigens, pregnancy features systemic and local increases in Tregs that support immune tolerance [ 2 - 4 ]. In mice, depletion of Tregs during the peri-implantation and early gestational windows causes implantation failure and increases embryo resorption, whereas their requirement for late gestational maintenance appears lower, indicating stage specificity [ 3 ]. Integrating evidence from humans and mice, Tregs support embryo invasion and placentation by limiting inflammation, suppressing effector T-cells, and modulating uterine artery remodeling and angiogenesis [ 4 , 5 ]. Qualitative differences among Treg subsets, such as peripherally induced Tregs (pTregs) and activated/effector Tregs, likely condition the peri-implantation immune milieu and influence pregnancy outcomes [ 4 , 5 ] (Figure 1 ). A conceptual bar graph illustrates the relative abundance of regulatory T-cells (Tregs) in the blood (systemic) compared to the uterus/decidua (local) at two key timepoints in early pregnancy: preimplantation (before embryo implantation) and placentation (when the placenta is establishing). At preimplantation, Treg levels are low both systemically and in the endometrium (baseline levels). By placentation, local Tregs (orange bars) in the decidua increase dramatically, reflecting their crucial role in promoting tolerance at the maternal-fetal interface. Systemic Tregs (blue bars) also rise modestly by placentation, but to a far lesser extent than local Tregs. The bar heights represent relative Treg quantities (arbitrary units), highlighting that decidual Tregs expand substantially with the progressing pregnancy, whereas circulating Tregs show a mild increase. All labels are clear (no overlap or cutoff text), and a legend distinguishes systemic vs. local Tregs Image credit: This is an original image created by the authors Sagiri Taguchi and Terumi Hayashi Immunologic infertility and Tregs In immune‑mediated infertility, including recurrent implantation failure and recurrent miscarriage, disruption of the Th1/Th2/Th17/Treg balance, together with quantitative reductions and qualitative dysfunction of Tregs, has been reported and is considered a key immunologic substrate of poor prognosis [ 4 , 6 ]. An appropriate Treg response in the early peri-implantation period promotes fetal acceptance, restrains excessive inflammation, and facilitates vascular remodeling, potentially influencing embryo transfer outcomes in assisted reproductive technologies (ARTs/in vitro fertilization) [ 4 , 5 ]. Endometriosis: Treg dysfunction and opportunities for disease modification Endometriosis is a disease in which ectopic endometrial tissue engrafts, proliferates, and progresses within a chronic inflammatory microenvironment; immune dysregulation is central to its pathophysiology [ 7 ]. In mouse models, Treg dysfunction (including experimental depletion) enhances local inflammation and angiogenesis and worsens the progression of endometriosis‑like lesions [ 7 ]. This supports a cascade of Treg breakdown, which contributes to heightened inflammation/angiogenesis resulting in lesion expansion [ 8 ]. Recent preclinical work further demonstrates that adoptive transfer (supplementation) of Tregs significantly suppresses the progression of endometriosis‑like lesions in Treg‑depleted mice, suggesting the feasibility of disease‑modifying intervention [ 9 ]. In nonhuman primates and humans, quantitative and functional Treg alterations have also been observed in association with endometriosis, bolstering the plausibility of clinical translation (Figure 2 ) [ 8 ]. This two-panel schematic separates Treg-directed therapies by their development status. The left panel (blue shaded) lists approaches remaining in preclinical research (no human trials yet), such as CAR Treg therapy, antigen-specific Treg therapies, and other emerging Treg-based treatments. The right panel (peach shaded) lists therapies that have entered clinical trials or clinical use, including polyclonal Treg therapy (adoptive Treg transfer tested in humans), low-dose IL-2 therapy (in clinical trials for autoimmune diseases), and tolerogenic DC therapy (tolerogenic dendritic cell vaccines tested in early trials). The two sections are distinctly colored to emphasize the division. All text labels are legible, with no truncation, facilitating a clear side-by-side comparison of therapies by stage of translation CAR: chimeric antigen receptor; IL-2: interleukin 2; DC: dendritic cell Image credit: This is an original image created by the authors Sagiri Taguchi and Terumi Hayashi Toward application in assisted reproductive medicine Tregs As Biomarkers Quantifying Treg abundance, phenotype, and function in peri-implantation endometrium or peripheral blood may enable stratification of recurrent implantation failure, individualized optimization of embryo transfer timing, and perioperative/peritransfer immunomonitoring [ 4 , 5 ]. Therapeutic Concepts Targeting Tregs Low‑dose interleukin‑2 (LD‑IL‑2) leverages the high‑affinity IL‑2 receptor (CD25) on Tregs to preferentially expand them; in graft‑versus‑host disease and autoimmune settings, restoration of Treg homeostasis with an acceptable safety profile has been demonstrated [ 10 - 12 ]. IL‑2 derivatives/complexes and other Treg‑biased agents are advancing clinically, offering scope for application to reproductive immunology alongside optimized dosing and delivery strategies [ 11 , 12 ]. Treg supplementation (adoptive transfer) has achieved proof of concept for attenuating lesion progression in endometriosis models and could be explored as pre‑ART conditioning or as an adjuvant to prevent postsurgical recurrence (Figure 3 ) [ 9 ]. A horizontal bar chart aligns various Treg-based therapeutic strategies with their approximate TRL (1-9). Each bar extends to the current readiness level of the approach (number at bar end). For example, polyclonal Treg therapy (expanded natural Tregs) is at an advanced preclinical/early clinical stage (around TRL 6), while CAR Treg therapy is earlier in development (around TRL 4). Strategies like low-dose IL-2 therapy (which expands Tregs in vivo) have reached clinical trials (around TRL 7), whereas tolerogenic DC therapy is in mid-development (TRL 5). Antigen-specific Treg therapies (e.g., tolerogenic vaccines) are still largely in proof-of-concept stages (TRL 3). All labels are clear and unbroken. The chart provides a comparative overview of how far along each Treg-based therapy is on the path from basic research to clinical application TRLs: technology readiness levels; CAR: chimeric antigen receptor; DC: dendritic cell Image credit: This is an original image created by the authors Sagiri Taguchi and Terumi Hayashi Pregnancy‑Acquired Memory Tregs and Preconditioning Pregnancy‑acquired, fetus‑antigen-specific “memory” Tregs have been reported to improve outcomes in subsequent gestations, supporting the concept of educational shaping of the Treg repertoire [ 13 ]. In ART, preconditioning (priming) of Tregs via the hormonal milieu and embryo- or seminal-plasma-derived signals, potentially combined with LD‑IL‑2, may synergize to induce and maintain memory Tregs [ 10 - 13 ]. Challenges for research and clinical implementation Standardization Harmonization of phenotypic and functional Treg assays in peripheral blood and endometrium, with prospective linkage to pregnancy outcomes, is required [ 4 - 6 ]. Stratified Trials Stepwise evaluation of LD‑IL‑2 dosing, safety, and efficacy in cohorts identified with Treg deficiency/dysfunction is needed [ 10 - 12 ]. Bridging for Cell Therapy Treg supplementation in endometriosis has preclinical proof of concept; determining optimal timing in humans (perioperative/peritransfer) and maintenance strategies (e.g., LD‑IL‑2 co‑administration) will be pivotal (Table 1 ) [ 9 - 12 ]. Trial designs must incorporate maternal-fetal safety monitoring, infection‑risk management, and evaluation of fetal development (Figure 4 ) [ 10 - 12 ]. IL-2: interleukin-2; LD-IL-2: low-dose interleukin-2; GVHD: graft-versus-host disease; AUC: area under the curve Developmental roadmap for Treg therapies. A schematic timeline depicts the phases of translation for Treg-based therapies, from inception to clinical practice. Four labeled stages are shown as boxes with arrows indicating the forward progression: Basic Research → Preclinical → Clinical Trials → Clinical Use. Basic Research denotes fundamental lab studies (e.g., mechanistic discoveries); preclinical involves animal models and safety/toxicity studies; Clinical Trials are the phased human trials (Phase I/II/III) testing safety and efficacy; clinical use represents approved therapies in routine medical practice. Bold black arrows connect each stage, visually indicating the flow from one stage to the next. The layout is clean and linear, with each stage clearly boxed and labeled (black text on white background) and no crowding or truncated text. This roadmap summarizes the stepwise progression required to bring Treg therapies from the lab bench to patient care in the clinic Image credit: This is an original image created by the authors Sagiri Taguchi and Terumi Hayashi

Tregs underpin the continuum from implantation to placentation through immune tolerance, and their significance as both mechanism and therapeutic target is increasingly established in immunologic infertility and endometriosis. The facts that Treg dysfunction exacerbates endometriosis and that Treg supplementation can suppress lesion progression strongly argue for the feasibility of immune interventions in reproductive medicine. Principles of immune tolerance highlighted by the Nobel scientific background map directly onto clinical trial designs, emphasizing stratification, optimal timing, and rational combinations.