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Cellular and Molecular Mechanisms in Immune Regulation—Second Edition

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

Deadline for manuscript submissions: 31 July 2026 | Viewed by 4143

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Special Issue Editors

Dr. Fábio Rinaldo Santori

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Guest Editor

Center for Molecular Medicine, University of Georgia, Athens, GA, USA
Interests: nuclear receptors; immunology; T cell biology; stem cells; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals

Dr. Natalia B. Ivanova

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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 Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Following the successful completion of the first edition of our Special Issue, titled “Cellular and Molecular Mechanisms in Immune Regulation”, we are pleased to announce the launch of its second edition.

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 how it is regulated by local tissues. In this Special Issue of Cells, entitled “Cellular and Molecular Mechanisms in Immune Regulation—Second Edition”, we will explore the following topics: 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, cancers, and autoimmune diseases.

We look forward to your contributions.

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

Manuscript Submission Information

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Keywords

innate immunity
dendritic cells
macrophages
T cells
B cells
cytokines
immunotherapy

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Published Papers (5 papers)

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Research

20 pages, 3530 KB

Open AccessArticle

Cardiolipin Induces CXCL9/CXCL10 Expression in Tumor-Infiltrating Lymphocytes

by Joana R. Lérias, Eric de Sousa, Carolina M. Gorgulho, Jéssica Kamiki, Patrícia A. António, Rodrigo Eduardo, Matilde Sedas, Nuno Figueiredo, Jian Han, Soon Seog Jeong, Ridong Chen and Markus J. Maeurer

Cells 2026, 15(9), 798; https://doi.org/10.3390/cells15090798 - 28 Apr 2026

Viewed by 203

Abstract

Background: Cardiolipin (CL) is a phospholipid composed of a glycerol linked with two phosphatidate moieties that constitutes an integral part of the human inner mitochondrial membrane under physiological conditions. It is also vital for bacterial membrane transport and key bacterial functions associated with cell division and infection. CL is released in the cytosol or into the extracellular milieu upon cell death and during inflammation. We therefore tested the ability of CL to activate and expand tumor infiltrating lymphocytes (TIL) from patients with epithelial cancer. Methods: TIL were isolated from gastrointestinal tumor tissues and expanded in vitro in the presence of CL. The role of the NLRP3 inflammasome was evaluated using the specific inhibitor MCC950 and siRNA-mediated silencing of NLRP3. Phenotypic changes and T-cell potency were assessed via CXCL9/10 expression levels. To characterize the immune repertoire, deep TCR sequencing was performed to compare the TCR Vα and Vβ CDR3 regions between TIL and the corresponding tumor tissue. Recognition of autologous tumor cells and tumor-specific mutations, including mutations in KRAS and mitochondrial UQCRFS1 (D145V), was assessed using MHC class I and II restriction assays. Results: CL-expanded TIL exhibited increased CXCL9/10 expression, which is associated with increased potency of tissue invasion. CL-TIL exhibited broader recognition of frequently occurring KRAS mutations, and this effect could be blocked with an inhibitor (MCC950) of the NLRP3 pathway, a multiprotein inflammatory complex associated with danger signaling. TIL exhibited an enriched TCR Vα and Vβ CDR3 repertoire compared to tumor tissue, as defined by deep TCR sequencing. TCR αβ+ TIL recognized autologous tumor tissue in an MHC class I– and class II–restricted fashion, including the mutant HLA-DP–restricted mitochondrial protein associated with the electron respiratory chain complex III (UQCRFS1 D145V) presented by autologous tumor cells. Conclusions: CL activates the NLRP3 inflammasome pathway in TIL from patients with GI cancer and increases CXCL9/CXCL10 expression in TIL, resulting in enhanced recognition of mutant cancer–associated target epitopes, including a mitochondrial protein. CL may provide a danger signal: that facilitates TIL expansion via CL-activated pathways. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation—Second Edition)

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16 pages, 3063 KB

Open AccessArticle

TGF-β Regulates CD8⁺ T Cell Memory by Triggering mTORC1^Weak-Mediated Activation of the Transcriptional FOXO1-TCF1-Eomes and Metabolic AMPK-ULK1-ATG7 Pathways

by Zhaojia Wu, Michelle Yu, Scot C Leary, Jianbo Yuan, Junqiong Huang and Jim Xiang

Cells 2026, 15(5), 471; https://doi.org/10.3390/cells15050471 - 5 Mar 2026

Viewed by 808

Abstract

CD8⁺ memory T (T_M) cells are essential for vaccine-induced protective immunity. While transforming growth factor beta (TGF-β) triggers CD8⁺ T_M cell differentiation, the underlying molecular mechanism(s) has yet to be uncovered. We therefore used a well-established cell culture protocol to prepare TGF-β-triggered CD8⁺ T_M cells derived from chicken ovalbumin (OVA)-specific T cell receptor (TCR) transgenic OTI mice, and systematically characterized them using Western blotting, confocal microscopy, flow cytometry and Seahorse assay analyses. We found that TGF-β/T cells exhibit a T_M cell phenotype (CD62L⁺KLRG1⁻) and display long-term survival upon adoptive transfer into mice. To elucidate the signaling circuitry underpinning the observed transcriptional and metabolic changes required to promote CD8⁺ T_M cell differentiation, we measured the expression of several critical factors and found that TGF-β triggered weak mTORC1 (mTORC1^Weak) signaling. mTORC1^Weak signaling in turn led to an increase in the abundance of key transcriptional (TCF1, FOXO1 and Eomes) and metabolic (AMPK-α1, ATG7, ULK1, SIRT1, OPA1 and LAL) factors and an elevation in mitochondrial mass and reliance on fatty acid oxidation (FAO). Our data thus reveal for the first time that TGF-β regulates CD8⁺ T cell memory by triggering mTORC1^Weak-mediated activation of the transcriptional FOXO1-TCF1-Eomes and metabolic AMPK-ULK1-ATG7 pathways. Given that induction of more qualified CD8⁺ T_M cells is one of the ultimate goals of vaccination, our findings identify additional targets critical to TGF-β-induced T cell memory, which may greatly impact future vaccine development for the treatment of cancer and infectious diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation—Second Edition)

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21 pages, 4799 KB

Open AccessFeature PaperArticle

Proinsulin-Loaded Nanoparticles Suppress Insulitis and Induce Temporary Diabetes Remission

by Maeva Agapoff, Chloé Dubreil, Emmanuelle Waeckel-Énée, Frédéric Geinguenaud, Valérie Manceau, Julien Diana, Barbara Bertocci, Laurence Motte and Peter van Endert

Cells 2026, 15(2), 174; https://doi.org/10.3390/cells15020174 - 19 Jan 2026

Viewed by 686

Abstract

Autoimmune type 1 diabetes (T1D) results from the failure of the physiologic regulatory mechanisms that are designed to maintain immune tolerance to pancreatic beta cells. Consequently, the design of strategies to restore tolerance to beta cell antigens is an attractive objective of translational research. We have designed ultrasmall nanoparticles (NPs) loaded with a proinsulin (PI) fusion protein and an agonist for the aryl hydrocarbon receptor (AhR), a transcription factor promoting tolerance induction by different immune cells. We report that a 4 week-treatment with these NPs in non-obese diabetic (NOD) mice starting at disease onset induces temporary and sometimes durable disease remission. Mechanistically, short-term NP treatment induces a rapid depletion of islet infiltrates with a dramatic reduction in the number of CD8⁺ T cells and dendritic cells. This is accompanied by the emergence of B lymphocytes producing IL-10. In the rare mice that undergo durable disease remission, the disappearance of islet infiltrates is associated with the emergence of Foxp3⁺ CD4⁺ regulatory T cells, IFN-γ-producing memory T cells in the spleen, and draining lymph nodes (LNs). We conclude that treatment with these NPs could be of interest in the treatment of recent-onset autoimmune diabetes, but is unlikely to be sufficient for the induction of long-term remission as a stand-alone therapy. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation—Second Edition)

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17 pages, 2618 KB

Open AccessArticle

Alterations in Resident Immune Cells in Prenatal Trisomy 21 Lungs

by Andrew Frauenpreis, Soumyaroop Bhattacharya, Randa Belgacemi, Pauline Sokolskiy, Gail Deutsch, Nicholas Jendzjowsky, Ian A. Glass, Thomas J. Mariani, Denise Al Alam and Soula Danopoulos

Cells 2025, 14(23), 1866; https://doi.org/10.3390/cells14231866 - 26 Nov 2025

Viewed by 710

Abstract

Respiratory tract infections (RTIs) are amongst the leading causes of hospitalizations in children with Down syndrome (DS). Their elevated susceptibility likely stems from structural differences in the airways and immune system abnormalities. The aim of this study was to characterize immune cells in prenatal Trisomy 21 (T21) lungs, potentially explaining vulnerability to RTIs. Single-cell RNA sequencing was used to profile immune cells in prenatal T21 (n = 5) and non-T21 (n = 4) prenatal lungs. Spatial phenotypes were assessed via fluorescent in situ hybridization and immunofluorescent staining on prenatal lung tissue sections. Gene expression analysis was also performed on isolated immune cells from lung single-cell suspensions. Several major immune cell populations were identified. A total of 84 DEGs were identified in at least 1 of the 14 different clusters. A significant decrease in the percentage of B cells was observed in T21 lungs (FDR = 0.0037, * p < 0.05). Furthermore, qRT-PCR demonstrated B cell markers were significantly decreased in T21, including those associated with B cell maturation (* p < 0.05 and ** p < 0.01). Several of these markers were also decreased at the protein level (i.e., CD20 and CD38; * p < 0.05 and ** p < 0.01). Our data demonstrate changes in the T21 pulmonary immune system in utero, primarily within the B cell population, which may contribute to the increased susceptibility to RTIs observed in children with DS. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation—Second Edition)

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20 pages, 4762 KB

Open AccessArticle

TNFR1 Suppression by XPro1595 Reduces Peripheral Neuropathies Associated with Perineural Invasion in Female Mice

by Morgan Zhang, Naijiang Liu, Kesava Asam, Charles Meng, Bradley Aouizerat and Yi Ye

Cells 2025, 14(22), 1749; https://doi.org/10.3390/cells14221749 - 7 Nov 2025

Cited by 2 | Viewed by 1179

Abstract

Perineural invasion (PNI), defined by cancer spreading or invading into the nerve, links to severe pain, recurrence, and poor prognosis. PNI contributes to nerve damage, Schwann cell activation, and sensory neuron dysfunction. Soluble tumor necrosis factor α (solTNFα) binds to TNFR1 to drive inflammation and nerve injury, playing a key role in cancer progression and pain. This study, using a mouse sciatic nerve PNI model, explored whether blocking solTNFα-TNFR1 signaling via TNFR1 knockout or pharmacological inhibition by XPro1595 could reduce PNI-associated pain. Data showed that XPro1595, but not TNFR1 knockout, reduced tumor burden, alleviated mechanical allodynia, and improved muscle function and locomotion, primarily in females. Histological analysis in females showed that XPro1595 increased the number of myelin and dendritic cells while reducing axonal damage that resulted from PNI. In the tumor zone outside the nerve truck, XPro1595 reduced T cell and increased macrophage and dendritic cell numbers. Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation—Second Edition)

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