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Cells
Special Issues
Cellular and Molecular Mechanisms in Immune Regulation
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Cellular and Molecular Mechanisms in Immune Regulation

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 11468

Special Issue Editors

Dr. Fábio Rinaldo Santori

E-Mail Website
Guest Editor
Center for Molecular Medicine, University of Georgia, Athens, GA, USA
Interests: nuclear receptors; immunology; T cell biology; stem cells; transcriptional regulation
Dr. Natalia B. Ivanova

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Center for Molecular Medicine, University of Georgia, Athens, GA, USA
Interests: epigenetics; stem cells; transcriptional regulation; hematopoiesis

Special Issue Information

Dear Colleagues,

Vaccines and immunotherapies for infectious diseases and cancer are key components of modern medicine. The next generation of immune therapies will come from a better understanding of how the immune system interacts and is regulated by local tissues. In this Special Issue of Cells entitled “Cellular and Molecular Mechanisms in Immune regulation”, we will explore topics such as the regulation of T cell maintenance in the periphery and formation of immunological memory, the role of innate immune cells and fibroblasts in wound healing, cancer and autoimmune diseases, the regulation of inflammation and the immune response by nerve cells, and the role of innate lymphoid cells (ILCs) in the development of lymphoid tissues. We also welcome manuscripts showing how these processes can be manipulated by biological therapies, monoclonal antibodies, and CAR T cells for the treatment of infections, cancer, and autoimmune diseases.

Dr. Fábio Rinaldo Santori
Dr. Natalia B. Ivanova
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • innate immunity
  • dendritic cells
  • macrophages
  • T cells
  • B cells
  • cytokines
  • immunotherapy

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Published Papers (8 papers)

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Research

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21 pages, 1497 KiB  
Article
Physiological Oxygen Levels in the Microenvironment Program Ex Vivo-Generated Conventional Dendritic Cells Toward a Tolerogenic Phenotype
by Antonia Peter, Morgane Vermeulen, Mats Van Delen, Amber Dams, Stefanie Peeters, Hans De Reu, Waleed F. A. Marei, Zwi N. Berneman and Nathalie Cools
Cells 2025, 14(10), 736; https://doi.org/10.3390/cells14100736 - 18 May 2025
Viewed by 299
Abstract
Dendritic cells (DCs) are critical regulators of immune homeostasis, balancing tolerance and immunity through antigen presentation and T cell modulation. While the influence of hypoxia (<2% O2) on DC function in pathological settings is well-documented, the impact of physiological O2 [...] Read more.
Dendritic cells (DCs) are critical regulators of immune homeostasis, balancing tolerance and immunity through antigen presentation and T cell modulation. While the influence of hypoxia (<2% O2) on DC function in pathological settings is well-documented, the impact of physiological O2 levels remains underexplored. This study investigates the role of physioxia (4% O2) in programming mature DCs toward a tolerogenic phenotype compared to atmospheric conditions (21% O2) typically present in in vitro assays. DC cultures generated under 4% O2 exhibited a reduced monocyte-to-DC transformation rate, increased lactate production, a semi-mature surface marker profile, and increased surface expression of the tolerance-associated marker ILT4. T cell priming was altered only when atmospheric DCs were co-cultured under physioxia, suggesting an O2-dependent threshold for immunostimulatory capacity. These findings highlight the complexity of O2-dependent mechanisms in DC-T cell interactions, revealing a delicate balance between tolerance and immunogenicity. Our results underscore the need for physiologically relevant O2 conditions in DC research to better reflect in vivo behavior and inform immunotherapy design. Overall, this study advances understanding of how microenvironmental cues shape DC biology, with implications for immune tolerance, autoimmunity, and cancer immunotherapy. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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20 pages, 2941 KiB  
Article
Immune Gene Expression Profiling in Individuals with Turner Syndrome, Graves’ Disease, and a Healthy Female by Single-Cell RNA Sequencing: A Comparative Study
by Soo Yeun Sim, In-Cheol Baek, Won Kyoung Cho, Min Ho Jung, Tai-Gyu Kim and Byung-Kyu Suh
Cells 2025, 14(2), 93; https://doi.org/10.3390/cells14020093 - 10 Jan 2025
Viewed by 1195
Abstract
Turner syndrome (TS) can be determined by karyotype analysis, marked by the loss of one X chromosome in females. However, the genes involved in autoimmunity in TS patients remain unclear. In this study, we aimed to analyze differences in immune gene expression between [...] Read more.
Turner syndrome (TS) can be determined by karyotype analysis, marked by the loss of one X chromosome in females. However, the genes involved in autoimmunity in TS patients remain unclear. In this study, we aimed to analyze differences in immune gene expression between a patient with TS, a healthy female, and a female patient with Graves’ disease using single-cell RNA sequencing (scRNA-seq) analysis of antigen-specific CD4(+) T cells. We identified 43 differentially expressed genes in the TS patient compared with the healthy female and the female patient with Graves’ disease. Many of these genes have previously been suggested to play a role in immune system regulation. This study provides valuable insights into the differences in immune-related gene expression between TS patients, healthy individuals, and those with autoimmune diseases. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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17 pages, 3365 KiB  
Article
Circulating T Cell Subsets in Type 1 Diabetes
by Aldo Ferreira-Hermosillo, Paola Santana-Sánchez, Ricardo Vaquero-García, Manuel R. García-Sáenz, Angélica Castro-Ríos, Adriana K. Chávez-Rueda, Rita A. Gómez-Díaz, Luis Chávez-Sánchez and María V. Legorreta-Haquet
Cells 2025, 14(1), 48; https://doi.org/10.3390/cells14010048 - 4 Jan 2025
Viewed by 1614
Abstract
Type 1 diabetes (T1D) is a complex disease driven by the immune system attacking the insulin-producing beta cells in the pancreas. Understanding the role of different T cell subpopulations in the development and progression of T1D is crucial. By employing flow cytometry to [...] Read more.
Type 1 diabetes (T1D) is a complex disease driven by the immune system attacking the insulin-producing beta cells in the pancreas. Understanding the role of different T cell subpopulations in the development and progression of T1D is crucial. By employing flow cytometry to compare the characteristics of T cells, we can pinpoint potential indicators of treatment response or therapeutic inefficacy. Our study reveals elevated prolactin (PRL) levels in T1D patients, along with a decreased production of key cytokines. Additionally, PD1 appears to play a significant role in T1D. Notably, PRL levels correlate with an earlier disease onset and a specific T cell phenotype, hinting at the potential influence of PRL. These findings highlight the need for further research to identify promising cellular targets for more effective and tailored therapies. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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16 pages, 1709 KiB  
Article
Differential Infiltration of Key Immune T-Cell Populations Across Malignancies Varying by Immunogenic Potential and the Likelihood of Response to Immunotherapy
by Islam Eljilany, Sam Coleman, Aik Choon Tan, Martin D. McCarter, John Carpten, Howard Colman, Abdul Rafeh Naqash, Igor Puzanov, Susanne M. Arnold, Michelle L. Churchman, Daniel Spakowicz, Bodour Salhia, Julian A. Marin-Acevedo, Shridar Ganesan, Aakrosh Ratan, Craig Shriver, Patrick Hwu, William S. Dalton, George J. Weiner, Jose R. Conejo-Garcia, Paulo Rodriguez and Ahmad A. Tarhiniadd Show full author list remove Hide full author list
Cells 2024, 13(23), 1993; https://doi.org/10.3390/cells13231993 - 3 Dec 2024
Viewed by 1981
Abstract
Background: Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate [...] Read more.
Background: Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers. Methods: We analyzed the mRNA co-expression levels of cellular biomarkers that define stem-like tumor-infiltrating lymphocytes (TILs), tissue-resident memory T-cells (TRM), early dysfunctional T-cells, late dysfunctional T-cells, activated-potentially anti-tumor (APA) T-cells and Butyrophilin 3A (BTN3A) isoforms, utilizing clinical and transcriptomic data from 1892 patients diagnosed with melanoma, bladder, ovarian, or pancreatic carcinomas. Real-world data were collected under the Total Cancer Care Protocol and the Avatar® project (NCT03977402) across 18 cancer centers. Furthermore, we compared the survival outcomes following immune checkpoint inhibitors (ICIs) based on immune cell gene expression. Results: In melanoma and bladder cancer, the estimated infiltration of APA T-cells differed significantly (p = 4.67 × 10−12 and p = 5.80 × 10−12, respectively) compared to ovarian and pancreatic cancers. Ovarian cancer had lower TRM T-cell infiltration than melanoma, bladder, and pancreatic (p = 2.23 × 10−8, 3.86 × 10−28, and 7.85 × 10−9, respectively). Similar trends were noted with stem-like, early, and late dysfunctional T-cells. Melanoma and ovarian expressed BTN3A isoforms more than other malignancies. Higher densities of stem-like TILs; TRM, early and late dysfunctional T-cells; APA T-cells; and BTN3A isoforms were associated with increased survival in melanoma (p = 0.0075, 0.00059, 0.013, 0.005, 0.0016, and 0.041, respectively). The TRM gene signature was a moderate predictor of survival in the melanoma cohort (AUROC = 0.65), with similar findings in testing independent public datasets of ICI-treated patients with melanoma (AUROC 0.61–0.64). Conclusions: Key cellular elements related to immune activation are more heavily infiltrated within ICI-responsive versus non-responsive malignancies, supporting a central role in anti-tumor immunity. In melanoma patients treated with ICIs, higher densities of stem-like TILs, TRM T-cells, early dysfunctional T-cells, late dysfunctional T-cells, APA T-cells, and BTN3A isoforms were associated with improved survival. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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21 pages, 3798 KiB  
Article
Identification of hsa_circ_0018905 as a New Potential Biomarker for Multiple Sclerosis
by Valeria Lodde, Ignazio Roberto Zarbo, Gabriele Farina, Aurora Masia, Paolo Solla, Ilaria Campesi, Giuseppe Delogu, Maria Rosaria Muroni, Dimitrios Tsitsipatis, Myriam Gorospe, Matteo Floris and Maria Laura Idda
Cells 2024, 13(19), 1668; https://doi.org/10.3390/cells13191668 - 9 Oct 2024
Cited by 1 | Viewed by 1406
Abstract
Multiple sclerosis (MS) is a demyelinating autoimmune disease characterized by early onset, for which the interaction of genetic and environmental factors is crucial. Dysregulation of the immune system as well as myelinization-de-myelinization has been shown to correlate with changes in RNA, including non-coding [...] Read more.
Multiple sclerosis (MS) is a demyelinating autoimmune disease characterized by early onset, for which the interaction of genetic and environmental factors is crucial. Dysregulation of the immune system as well as myelinization-de-myelinization has been shown to correlate with changes in RNA, including non-coding RNAs. Recently, circular RNAs (circRNAs) have emerged as a key player in the complex network of gene dysregulation associated with MS. Despite several efforts, the mechanisms driving circRNA regulation and dysregulation in MS still need to be properly elucidated. Here, we explore the panorama of circRNA expression in PBMCs purified from five newly diagnosed MS patients and five healthy controls (HCs) using the Arraystar Human circRNAs microarray. Experimental validation was then carried out in a validation cohort, and a possible correlation with disease severity was tested. We identified 64 differentially expressed circRNAs, 53 of which were downregulated in PBMCs purified from MS compared to the HCs. The discovery dataset was subsequently validated using qRT-PCR with an independent cohort of 20 RRMS patients and 20 HCs. We validated seven circRNAs differentially expressed in the RRMS group versus the HC group. hsa_circ_0000518, hsa_circ_0000517, hsa_circ_0000514, and hsa_circ_0000511 were significantly upregulated in the MS group, while hsa_circ_0018905, hsa_circ_0048764, and hsa_circ_0003445 were significantly downregulated; Among them, the expression level of hsa_circ_0018905 was significantly decreased in patients showing a higher level of disability and in progressive forms of MS. We described the circRNAs expression profile of PBMCs in newly diagnosed MS patients and proposed hsa_circ_0018905 as potential MS biomarker. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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Review

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29 pages, 4473 KiB  
Review
Role of T Follicular Helper Cells in Viral Infections and Vaccine Design
by Sohrab Ahmadivand, Robert Fux and Dušan Palić
Cells 2025, 14(7), 508; https://doi.org/10.3390/cells14070508 - 29 Mar 2025
Viewed by 787
Abstract
T follicular helper (Tfh) cells are a specialized subset of CD4+ T lymphocytes that are essential for the development of long-lasting humoral immunity. Tfh cells facilitate B lymphocyte maturation, promote germinal center formation, and drive high-affinity antibody production. Our current knowledge of Tfh [...] Read more.
T follicular helper (Tfh) cells are a specialized subset of CD4+ T lymphocytes that are essential for the development of long-lasting humoral immunity. Tfh cells facilitate B lymphocyte maturation, promote germinal center formation, and drive high-affinity antibody production. Our current knowledge of Tfh interactions with the humoral immune system effectors suggests that they have a critical role in supporting the immune response against viral infections. This review discusses the mechanisms through which Tfh cells influence anti-viral immunity, highlighting their interactions with B cells and their impact on antibody quality and quantity. We explore the role of Tfh cells in viral infections and examine how vaccine design can be improved to enhance Tfh cell responses. Innovative vaccine platforms, such as mRNA vaccines and self-assembling protein nanoplatforms (SAPNs), are promising strategies to enhance Tfh cell activation. Their integration and synergistic combination could further enhance immunity and Tfh responses (SAPN-RNA vaccines). In summary, we provide a comprehensive overview of the current insights into Tfh cells’ role during viral infections, emphasizing their potential as strategic targets for innovative vaccine development. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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13 pages, 409 KiB  
Review
Ultraviolet Radiation-Induced Tolerogenic Dendritic Cells in Skin: Insights and Mechanisms
by Gelare Ghajar-Rahimi, Nabiha Yusuf and Hui Xu
Cells 2025, 14(4), 308; https://doi.org/10.3390/cells14040308 - 18 Feb 2025
Viewed by 1010
Abstract
Ultraviolet (UV) radiation has profound effects on the immune system, including the induction of tolerogenic dendritic cells (DCs), which contribute to immune suppression and tolerance. This review explores the roles of conventional CD11c⁺ DCs, as well as cutaneous Langerhans cells and CD11b⁺ myeloid [...] Read more.
Ultraviolet (UV) radiation has profound effects on the immune system, including the induction of tolerogenic dendritic cells (DCs), which contribute to immune suppression and tolerance. This review explores the roles of conventional CD11c⁺ DCs, as well as cutaneous Langerhans cells and CD11b⁺ myeloid cells, in UV-induced immune modulation. Two key mechanisms underlying the immunosuppressive relationship between UV and DCs are discussed: the inactivation of DCs and the induction of tolerogenic DCs. DCs serve as a critical link between the innate and adaptive immune systems, serving as professional antigen-presenting cells. In this context, we explore how UV-induced DCs influence the activity of specific T cell subsets, including regulatory T lymphocytes and T helper cells, and shape immune outcomes. Finally, we highlight the implications of UV-induced tolerogenic DCs in select dermatologic pathologies, including cutaneous lupus, polymorphic light eruption, and skin cancer. Understanding the mechanisms by which UV radiation alters DC function offers insights into the complex interplay between environmental factors and immune regulation, providing potential avenues for preventive and therapeutic intervention in UV-induced skin diseases. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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24 pages, 493 KiB  
Review
Molecular Mechanisms of Immune Regulation: A Review
by Borros Arneth
Cells 2025, 14(4), 283; https://doi.org/10.3390/cells14040283 - 14 Feb 2025
Viewed by 1778
Abstract
Background: The immune system must carefully balance fighting pathogens with minimization of inflammation and avoidance of autoimmune responses. Over the past ten years, researchers have extensively studied the mechanisms regulating this delicate balance. Comprehending these mechanisms is essential for developing treatments for inflammatory [...] Read more.
Background: The immune system must carefully balance fighting pathogens with minimization of inflammation and avoidance of autoimmune responses. Over the past ten years, researchers have extensively studied the mechanisms regulating this delicate balance. Comprehending these mechanisms is essential for developing treatments for inflammatory conditions. Aim: This review aims to synthesize knowledge of immunoregulatory processes published from 2014–2024 and to highlight discoveries that provide fresh perspectives on this complex balance. Methods: The keywords “molecular mechanisms”, “immune regulation”, “immune signaling pathways”, and “immune homeostasis” were used to search PubMed for articles published between 2014 and 2024, with a preference for articles published in the past three years. Results: Recent research has pinpointed the impact of factors such as cytokine signaling, T-cell regulation, epigenetic regulation, and immunometabolism on immune function. Discussion: New research highlights the intricate interactions between the immune system and other molecular elements. A key area of interest is the impact of non-coding RNAs and metabolic pathways on the regulation of immune responses. Conclusions: Exploring the mechanisms by which the immune system is regulated will provide new avenues for developing treatments to address autoimmune and inflammatory conditions. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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