Immune tolerance is a crucial physiological mechanism by which the immune system distinguishes self from non-self antigens, thereby preventing excessive or autoimmune responses. Among its various forms, peripheral immune tolerance plays a pivotal role in maintaining immune homeostasis (1, 2). In 1990, Corbel and colleagues (3) demonstrated that peripheral immune tolerance could be established against exogenous antigens in the peripheral tissues of chicken embryos, providing direct evidence for the existence of peripheral immune tolerance.

Over the past 3 decades, remarkable progress has been made in elucidating the molecular mechanisms underlying peripheral immune tolerance. This mechanism has shown broad applicability in organ transplantation (4), the treatment of autoimmune diseases (5), allergen desensitization (6), and tumor immunosuppression (7). When the function of peripheral immune tolerance is impaired, it can lead to the development of autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes (8). Therefore, a comprehensive understanding of the regulatory mechanisms and pathological roles of peripheral immune tolerance is of great significance for both basic immunological research and clinical translation.

However, as research directions within this field have diversified, the overall landscape, knowledge structure, and emerging hotspots of peripheral immune tolerance have become increasingly complex. The absence of systematic quantitative analyses has hindered accurate identification of research trends, key contributors, and potential frontiers. Consequently, a global bibliometric assessment of this field is warranted to elucidate its academic evolution and future development trajectories.

Bibliometrics is a well-established and efficient tool for literature review and thematic mining, capable of quantitatively revealing the overall structure and dynamic evolution of a research field (9). Applying bibliometric methods to the study of peripheral immune tolerance facilitates a comprehensive depiction of its publication trends, core scholars and institutions, international collaboration patterns, and thematic evolution pathways. Such analysis not only uncovers theknowledge base and research hotspots of the discipline but also provides valuable insights and guidance for future studies focusing on mechanistic exploration, clinical translation, and cross-disciplinary applications. Based on this rationale, the present study systematically retrieved and integrated literature related to peripheral immune tolerance from the Web of Science Core Collection and Scopus databases. Using VOSviewer, CiteSpace, RStudio Biblioshiny, and OriginPro, a comprehensive bibliometric and visualization analysis was conducted to delineate the global research landscape, knowledge structure, emerging topics, and development trends of this field from 1989 to 2025.

Clinically, peripheral immune tolerance serves as the biological foundation for both the prevention of autoimmune diseases and the reduction of transplant rejection (23). It is also frequently exploited by the tumor microenvironment to achieve immune evasion (19). Consequently, it has become a key target for immune regulation and translational therapy. In bibliometrics, the results are often subjective and descriptive in nature (24). Therefore, how to ensure that the analysis provides practical and meaningful insights is a critical issue. In this study, data from the Web of Science Core Collection and Scopus databases were retrieved, integrated, and analyzed using multiple bibliometric and visualization tools. A systematic bibliometric analysis was conducted to explore publication trends, keyword evolution, collaborative networks of countries, institutions, and authors, as well as citation patterns and journal distributions in the field of peripheral immune tolerance. This analysis identified the research hotspots, academic core networks, and potential knowledge gaps, providing valuable insights and reference for future studies in project development, mechanistic exploration, targeted drug discovery, autoimmune disease therapy, and scientific knowledge dissemination.

Over the past three decades, the number of publications on peripheral immune tolerance has shown an overall upward trend since the 1990s, reaching its peak around 2008 and gradually declining thereafter. Several external structural factors may have contributed to the decline in publication output after 2008. First, since 2000, the global number of academic journals has increased substantially due to the expansion of open-access and online publishing models. For example, an analysis of Scopus-indexed journals showed that approximately 41.6% of the indexed titles were added between 2000 and 2019, representing more than 11,000 newly indexed journals during this period. Second, changes in the coverage and indexing policies of bibliographic databases may affect longitudinal retrieval trends. Both Scopus and Web of Science regularly revise their content selection criteria and indexing policies, which could partly account for this pattern. Third, over the past decade, the scientific influence of previously dominant immunology journals has gradually declined. For instance, The Journal of Immunology reached a minor peak in 2009 with 1,891 publications, but its annual output sharply dropped to 369 papers by 2024, reflecting a notable contraction in the peripheral immune tolerance literature. Fourth, following the identification of key immune checkpoints such as PD-1/PD-L1 and the rise of cancer immunotherapy, the research focus gradually shifted from fundamental tolerance mechanisms toward tumor immunology and clinical applications (25). For instance, since 2015, PD-1/PD-L1–based immunotherapies have become the standard treatments for multiple malignancies (26). Furthermore, evolutionary therapeutic approaches were also extensively explored during that period, including chimeric antigen receptor regulatory T cells (CAR-Treg) and antigen-specific Treg strategies. These approaches enhance the antigen specificity and stability of Treg cells through genetic engineering, representing an important step in translating fundamental mechanisms of immune tolerance into clinical applications (27, 28). This paradigm shift has inevitably reduced scholarly attention toward the “traditional” field of peripheral immune tolerance, resulting in a gradual decline in both publication output and citation frequency since 2008. Fifth, the declining interest in classical tolerance models—most notably Type 1 diabetes (T1D)—also likely contributes to the apparent reduction in publication counts in recent years. For several decades, T1D was one of the dominant disease models for studying peripheral immune tolerance breakdown, autoreactive T cells and strategies for antigen-specific tolerance induction, particularly through the NOD mouse and early clinical trials. However, more recent work has progressively shifted the T1D field toward broader questions of disease heterogeneity, β-cell stress biology and multi-omics–based endotyping, rather than focusing exclusively on tolerance mechanisms. In their comprehensive Lancet Seminar, Atkinson and colleagues emphasized that recent advances have largely concentrated on genetic risk, environmental modifiers, pancreatic pathology and improved clinical management, while immune tolerance–directed interventions represent only one component within a much wider pathogenic framework (29). At the same time, translational efforts in T1D have become increasingly focused on specific interventional strategies, such as adoptive transfer of regulatory T cells, rather than on classical tolerance models per se. For example, Bluestone and colleagues reported a phase 1 trial in which ex vivo–expanded autologous polyclonal Tregs were infused into patients with recent-onset T1D, demonstrating safety and persistence of the transferred cells, and representing a concrete step toward cell-based immunotherapy (16). Taken together, these trends suggest that classical models like T1D, while still important, no longer occupy the same central position as “prototypic tolerance models” in the literature. This thematic shift—from disease-specific tolerance models to broader questions of immune regulation, tissue microenvironments and targeted interventions—likely contributes to the observed decline in publications explicitly tagged with traditional tolerance-model keywords.

It is worth noting that Sakaguchi proposed the concept of regulatory T cells (Tregs) and demonstrated their pivotal role in immune tolerance in 1995 (17), which led to a rapid surge in related research. For this groundbreaking discovery, Shimon Sakaguchi, together with Fred Ramsdell and Mary E. Brunkow, was awarded the 2025 Nobel Prize in Physiology or Medicine. With the 2025 Nobel Prize recognizing seminal contributions to this area, research interest in peripheral immune tolerance is expected to experience renewed growth in the coming years.

Through the analysis of large-scale keyword data, it is evident that “autoimmunity” and “Treg/FOXP3” have long remained the central research foci in the field of immune tolerance. This is closely related to the mechanism by which failure of peripheral immune tolerance directly triggers autoimmune diseases: once tolerance is lost, self-reactive effector cells can mediate inflammatory immune responses (30). The FOXP3 gene functions as the master regulatory switch of Treg cells, controlling their development and function, thereby maintaining immune tolerance (20). This factor reprograms CD4 by interacting with co factors such as NFAT and Runx1 to enhance T cell activity, thereby increasing the expression of inhibitory molecules including CD25 and CTLA-4, while inhibiting effector genes such as IL2 and IFNG (31) FOXP3 suppresses excessive immune responses, prevents the onset of autoimmune diseases, and also plays critical roles in tumor immunity and transplantation tolerance. Mutations in this gene can lead to severe autoimmune disorders such as IPEX syndrome (32, 33). Consistent with these mechanistic foundations, accumulating clinical evidence further underscores that disruptions in Treg number and function represent a common pathway driving diverse immune-mediated diseases. In vitiligo, two recent meta-analyses demonstrated significantly reduced Treg frequency, impaired suppression of CD4⁺ and CD8⁺ T cells, and decreased expression of FOXP3, IL-10, and TGF-β in both skin and blood, with disease activity correlating with the magnitude of Treg dysfunction (34, 35). Importantly, therapeutic interventions capable of restoring Treg function—such as narrow-band UVB or Treg-modulating treatments—were associated with increases in Treg frequency and FOXP3 expression, highlighting the translational relevance of tolerance restoration. Beyond autoimmunity, FOXP3⁺ Tregs also exert context-dependent effects in cancer. A systematic review of 76 studies showed that high intratumoral Treg infiltration was generally associated with poorer overall survival in many solid tumors, whereas it correlated with improved outcomes in certain cancers such as colorectal, head and neck, and esophageal malignancies (36). Together, these findings illustrate that Treg dysregulation—whether through numerical deficiency, impaired suppressive capacity, or altered tissue localization—serves as a unifying immunological mechanism across autoimmune disease and cancer, reinforcing the centrality of FOXP3-mediated pathways in shaping peripheral immune tolerance.

As shown in Figure 4, recent trending topics emphasize how peripheral immune tolerance is increasingly being investigated within specific disease and therapeutic contexts rather than under traditional mechanistic labels. “Systemic lupus erythematosus (SLE)” represents a prototypical systemic autoimmune disorder in which the breakdown of peripheral immune tolerance to nuclear self-antigens leads to autoantibody production and multi-organ damage. Current therapeutic strategies, including B cell–targeted agents and emerging Treg-based approaches, are partly aimed at restoring defective peripheral immune tolerance (37). “Treg cells” and “FOXP3” denote the core cellular and transcriptional regulators responsible for enhancing peripheral immune tolerance, as discussed earlier. The keyword “tumor microenvironment” reflects growing interest in how tumors exploit peripheral immune tolerance mechanisms: within this milieu, Treg cells can be recruited and accumulate abundantly, acting as one of the major barriers to effective antitumor immune responses (38). PD-1 is an inhibitory receptor expressed on activated T and B cells, playing a critical role in regulating peripheral immune tolerance (18). The interaction between PD-1 and its ligand PD-L1 suppresses T-cell activation and enhances tumor immune tolerance (39).The emergence of “immune checkpoint inhibitors” and “PD-1/PD-L1” indicates a complementary trend, wherein peripheral immune tolerance pathways are intentionally disrupted to potentiate anti-tumor immune responses. This highlights that the same checkpoints maintaining self-tolerance can serve as therapeutic targets in cancer immunotherapy (40). Consequently, research on PD-1–related tumor immune pathways has increased in recent years, making PD-1/PD-L1 one of the most frequently appearing and intensively studied keywords within the domain of peripheral immune tolerance. Finally, the appearance of “nanoparticles” underscores the rapid advancement of biomaterial-based delivery systems designed to promote antigen-specific peripheral immune tolerance in autoimmune diseases and transplantation, offering promising avenues for novel targeted therapeutics (41).

Collectively, these emerging keywords suggest that although the explicit use of traditional terminology has declined, research on peripheral immune tolerance is being restructured around specific clinical contexts and intervention strategies, reflecting an evolution from mechanistic studies toward translational and application-oriented paradigms.

National research output reflects the development status of a country’s scientific capacity. Bibliometric analysis helps compare research input–output efficiency across countries and identify patterns of international collaboration (42, 43). In the field of peripheral immune tolerance, countries such as the United States, Germany, and China have contributed the majority of research outputs. The United States has maintained a dominant position, leading with 1,351 publications and 143,081 citations, thereby exerting a strong influence on research directions. It also serves as the central hub in the international collaboration network, exhibiting the highest collaboration strength. The institution with the largest number of publications is Harvard University, with 90 papers and the highest citation count (10,768), reflecting its core leadership in this field. The most productive author is Roncarolo Maria Grazia, who has published 23 papers with 9,801 citations. Tables 1, 3 provide valuable references for identifying potential collaborating institutions and authors for future research. However, a higher publication count does not necessarily indicate a greater likelihood of future collaboration. Several highly productive authors were most active in earlier decades and are no longer contributing to current research trends. For example, although Weiner, Howard L. has accumulated a substantial citation count (6,548 citations), his active involvement in the field of peripheral immune tolerance largely ceased around 2010, suggesting that his research focus has shifted to other areas. Consequently, identifying meaningful collaboration opportunities requires prioritizing authors based not only on overall influence but also on their recent years of activity. Modern bibliometric platforms support such refined assessments; for instance, the Web of Science Core Collection allows users to query authors by ORCID, enabling the retrieval of both their high-impact publications and their most recent output. These tools help investigators more accurately identify active and influential collaborators who are currently shaping the field. To sum up, such cross-national collaboration facilitates resource sharing and knowledge exchange, and is expected to further advance research on immune tolerance toward deeper mechanistic insights and translational applications.

In addition, an in-depth analysis was performed on the highly cited and co-cited publications in the field of peripheral immune tolerance. The most frequently cited publication was the landmark paper by Sakaguchi (17) in the Journal of Immunology, which was the first to systematically demonstrate that regulatory T cells (Tregs) play a critical role in maintaining peripheral immune tolerance and preventing autoimmune responses. This study laid the foundational framework for the Treg concept (17). Subsequent highly cited studies—most notably those by Freeman (18) and Curiel (19)—further established the theoretical and methodological basis of this field. These seminal works defined the immunosuppressive functions of the Treg lineage, elucidated the regulatory mechanisms of the immune checkpoint molecule PD-1/PD-L1, and revealed the core pathways of immune evasion within the tumor microenvironment (18, 19). The most recent co-citation burst was observed for the review by Domínguez-Villar (22) published in Nature Immunology, which provided a comprehensive summary of the roles and dysregulation mechanisms of Treg cells in autoimmune diseases (22).

In Figure 6, two publications stand out as being both highly cited and highly co-cited: Steinman RM, 2003, Annu. Rev. Immunol. and Vignali DAA, 2008, Nat. Rev. Immunol. The former discusses the role of dendritic cells (DCs) in the induction of immune tolerance (44), while the latter provides a systematic review of the mechanisms underlying Treg-mediated suppression, highlighting their context-dependent and complementary nature (45). Together, these landmark studies represent the intellectual backbone of peripheral immune tolerance research and serve as essential references for future investigators seeking to advance understanding of immune regulation, tolerance induction, and translational immunotherapy.

The major research findings in the field of peripheral immune tolerance have predominantly been published in specialized immunology journals. The Journal of Immunology is the most prolific journal, with 302 publications and a total of 28,375 citations. The highest impact factor is observed for Nature Immunology, with an impact factor of 27.6 in 2025. Within tolerance-related research, Frontiers in Immunology has emerged as one of the most popular and active publication platforms. By examining journal publication volume, citation frequency, and impact indicators, we visualized these results in Figure 7, providing robust data support for future researchers to identify suitable journals for dissemination and to facilitate the continuous development and advancement of research on peripheral immune tolerance.

It is worth noting that Gao et al. conducted a bibliometric analysis of global research trends on regulatory T cells in neurological diseases and found that the United States was the most productive country, followed by China. Frontiers in Immunology was identified as the leading publication venue in this field, and keywords such as ‘regulatory T cells,’ ‘autoimmunity,’ and ‘inflammation’ were among the most frequently used author keywords (46). These findings are largely consistent with our results, further highlighting the dominant contributions of the United States and China in Treg-related research, as well as the central role of terms like Treg/FOXP3 and autoimmunity in global research hotspots.

Several limitations should be acknowledged in this study. First, all data were retrieved exclusively from the Web of Science Core Collection and Scopus databases. Although these two sources represent the most authoritative repositories for bibliometric analysis, they do not encompass all relevant publications—particularly book chapters and conference proceedings. In addition, PubMed was excluded due to its incomplete citation metadata and lower compatibility with bibliometric tools compared with Web of Science and Scopus. Including PubMed data might introduce considerable bias to the overall analysis, although some valuable insights may be missed as a result. Second, bibliometric analysis primarily emphasizes quantitative indicators—such as publication counts, citation frequencies, and co-occurrence strength—which may not fully capture the qualitative scientific impact or innovation of individual studies. For instance, recent high-quality publications that have not yet accumulated sufficient citations may be underrepresented. Therefore, continuous updates and integration of dynamic citation data will be necessary in future studies to ensure that bibliometric assessments remain accurate and reflective of current research trends.