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Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 10824

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Special Issue Editors

Prof. Dr. Benito Antonio Yard

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Guest Editor

Vth Medical Department, University Hospital Mannheim, Clinical Faculty Mannheim, University of Heidelberg, 69047 Heidelberg, Germany
Interests: immunology; renal transplantation; diabetes; diabetic nephropathy; ANCA associated vasculitis; auto-immunity

Prof. Dr. Jan Leipe

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Guest Editor

Vth Medical Department, University Hospital Mannheim, Clinical Faculty Mannheim, University of Heidelberg, 69047 Heidelberg, Germany
Interests: rheumatology; Th commitment; psoriasis arthritis; Th17; checkpoint inhibitors; cytokines

Special Issue Information

Dear Colleagues,

Modulation of acquired immunity has garnered significant attention and is on the verge of becoming a mainstay treatment in cancer immunotherapy. While in the latter, therapeutic targeting of immune checkpoints aims to augment immune responses, in autoimmunity the same pathways need to be targeted in opposite direction to restrain an over-excited immune response. Since tumor-mediated immune escape partly involves suppression of innate immune sensing, innate immune checkpoints may also serve as potential targets for cancer immunotherapy. Likewise, aberrant activation and regulation of innate immune checkpoints, such as the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, may have important roles in the initiation and maintenance of autoimmune diseases. Notwithstanding its clinical success, a significant number of patients on checkpoint inhibitors develop immune-related adverse events (irAEs) affecting a wide variety of organs. Our overall understanding of how modulation of immune checkpoints might impact balances in the immune system is therefor of fundamental importance for the development of new therapeutic modalities.

This Special Issue of IJMS seeks original research and review articles that discuss mechanisms and means of immune modulation in innate and adaptive immunity. Contributions with focus on molecular and mechanistic issues in current immunotherapy in the fields of cancer, auto-immunity and transplantation are particularly welcomed.

Prof. Dr. Benito Antonio Yard
Prof. Dr. Jan Leipe
Guest Editors

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Keywords

immune checkpoints
innate immunity
adaptive immunity
modulation

Published Papers (7 papers)

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Research

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21 pages, 6650 KiB

Open AccessArticle

Duality of Valproic Acid Effects on Inflammation, Oxidative Stress and Autophagy in Human Eosinophilic Cells

by Goksu Uzel, Ece Oylumlu, Lubeyne Durmus and Ceren Ciraci

Int. J. Mol. Sci. 2023, 24(17), 13446; https://doi.org/10.3390/ijms241713446 - 30 Aug 2023

Cited by 2 | Viewed by 1227

Abstract

Eosinophils function in rapid innate immune responses and allergic reactions. Recent research has raised the possibility that the histone deacetylase inhibitor valproic acid (VPA) may be a promising therapeutic agent for treatment of allergic responses and certain cancers. However, its effects on eosinophils remain unclear. Utilizing the EoL-1 human eosinophil cell line as a model, we investigated the effects of VPA on oxidative stress- and autophagy-mediated immune responses. We found that VPA induced reactive oxidative species (ROS) generation and eosinophil activation without affecting cell viability. Moreover, VPA treatment suppressed the negative regulator of antioxidant transcription factor Nrf2, which is known to activate antioxidant defense. Interestingly, VPA was able to increase autophagic markers, as well as NLRP3 and NLRC4 mRNA activation, in Eol-1 cells in a dose-dependent manner. Collectively, our results indicate that VPA could increase the severity of allergic responses, and if so, it clearly would not be a suitable drug for the treatment of allergic reactions. However, VPA does have the potential to induce autophagy and to regulate the inflammatory responses via inflammasome-driven caspase-1 deactivation in a dose-dependent manner. Full article

(This article belongs to the Special Issue Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity)

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17 pages, 3772 KiB

Open AccessArticle

Lipopolysaccharide Tolerance in Human Primary Monocytes and Polarized Macrophages

by Hui Li, Annette Breedijk, Nadine Dietrich, Katja Nitschke, Jonas Jarczyk, Philipp Nuhn, Bernhard K. Krämer, Benito A. Yard, Jan Leipe and Sibylle Hauske

Int. J. Mol. Sci. 2023, 24(15), 12196; https://doi.org/10.3390/ijms241512196 - 30 Jul 2023

Cited by 1 | Viewed by 1216

Abstract

Innate immune memory allows macrophages to adequately respond to pathogens to which they have been pre-exposed. To what extent different pattern recognition receptors, cytokines and resolution signals influence innate immune memory needs further elucidation. The present study assessed whether lipopolysaccharide (LPS) tolerance in monocytes and macrophages is affected by these factors. Human CD14⁺ cells were isolated from peripheral blood, stimulated by LPS and re-stimulated after 3 days of resting. Hereafter, immune-responsive gene 1 (IRG-1), heme oxygenase 1 (HO-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expression were assessed. Our study revealed the following findings: (1) While pre-stimulation with the Toll-like receptor 4 ligand LPS inhibits the induction of IRG-1, TNF-α and IL-6 expression, pre-stimulation with TLR 1/2 ligands only affects cytokine production but not IRG-1 expression upon subsequent TLR4 engagement. (2) Prior TNF-α stimulation does not affect LPS tolerance but rather increases LPS-mediated cytokine expression. (3) Dimethyl itaconate (DMI) inhibits the expression of IRG-1 in a dose-dependent manner but does not affect TNF-α or IL-6 expression. (4) Docosahexaenoic acid (DHA) partly inhibits IRG-1 expression in monocytes but not in M_(IFNγ) and M_(IL-4) polarized macrophages. LPS tolerance is not affected in these cells by DHA. The data presented in this study partly corroborate and extend previous findings on innate immune memory and warrant further studies on LPS tolerance to gain a better understanding of innate immune memory at the molecular level. Full article

(This article belongs to the Special Issue Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity)

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15 pages, 3059 KiB

Open AccessArticle

Functional Analysis of a CTL-X-Type Lectin CTL16 in Development and Innate Immunity of Tribolium castaneum

by Jingxiu Bi, Yutao Wang, Rui Gao, Pingxiang Liu, Yuying Jiang, Lei Gao, Bin Li, Qisheng Song and Mingxiao Ning

Int. J. Mol. Sci. 2023, 24(13), 10700; https://doi.org/10.3390/ijms241310700 - 27 Jun 2023

Viewed by 1014

Abstract

C-type lectins (CTLs) are a class of proteins containing carbohydrate recognition domains (CRDs), which are characteristic modules that recognize various glycoconjugates and function primarily in immunity. CTLs have been reported to affect growth and development and positively regulate innate immunity in Tribolium castaneum. However, the regulatory mechanisms of TcCTL16 proteins are still unclear. Here, spatiotemporal analyses displayed that TcCTL16 was highly expressed in late pupae and early adults. TcCTL16 RNA interference in early larvae shortened their body length and narrowed their body width, leading to the death of 98% of the larvae in the pupal stage. Further analysis found that the expression level of muscle-regulation-related genes, including cut, vestigial, erect wing, apterous, and spalt major, and muscle-composition-related genes, including Myosin heavy chain and Myosin light chain, were obviously down-regulated after TcCTL16 silencing in T. castaneum. In addition, the transcription of TcCTL16 was mainly distributed in the hemolymph. TcCTL16 was significantly upregulated after challenges with lipopolysaccharides, peptidoglycans, Escherichia coli, and Staphylococcus aureus. Recombinant CRDs of TcCTL16 bind directly to the tested bacteria (except Bacillus subtilis); they also induce extensive bacterial agglutination in the presence of Ca²⁺. On the contrary, after TcCTL16 silencing in the late larval stage, T. castaneum were able to develop normally. Moreover, the transcript levels of seven antimicrobial peptide genes (attacin2, defensins1, defensins2, coleoptericin1, coleoptericin2, cecropins2, and cecropins3) and one transcription factor gene (relish) were significantly increased under E. coli challenge and led to an increased survival rate of T. castaneum when infected with S. aureus or E. coli, suggesting that TcCTL16 deficiency could be compensated for by increasing AMP expression via the IMD pathways in T. castaneum. In conclusion, this study found that TcCTL16 could be involved in developmental regulation in early larvae and compensate for the loss of CTL function by regulating the expression of AMPs in late larvae, thus laying a solid foundation for further studies on T. castaneum CTLs. Full article

(This article belongs to the Special Issue Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity)

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24 pages, 2682 KiB

Open AccessArticle

Beneficial Effects of Tacrolimus on Brain-Death-Associated Right Ventricular Dysfunction in Pigs

by Asmae Belhaj, Laurence Dewachter, Astrid Monier, Gregory Vegh, Sandrine Rorive, Myriam Remmelink, Mélanie Closset, Christian Melot, Jacques Creteur, Isabelle Salmon and Benoît Rondelet

Int. J. Mol. Sci. 2023, 24(13), 10439; https://doi.org/10.3390/ijms241310439 - 21 Jun 2023

Cited by 1 | Viewed by 959

Abstract

Background: Right ventricular (RV) dysfunction remains a major problem after heart transplantation and may be associated with brain death (BD) in a donor. A calcineurin inhibitor tacrolimus was recently found to have beneficial effects on heart function. Here, we examined whether tacrolimus might prevent BD-induced RV dysfunction and the associated pathobiological changes. Methods: After randomized tacrolimus (n = 8; 0.05 mg·kg⁻¹·day⁻¹) or placebo (n = 9) pretreatment, pigs were assigned to a BD procedure and hemodynamically investigated 1, 3, 5, and 7 h after the Cushing reflex. After euthanasia, myocardial tissue was sampled for pathobiological evaluation. Seven pigs were used as controls. Results: Calcineurin inhibition prevented increases in pulmonary vascular resistance and RV-arterial decoupling induced by BD. BD was associated with an increased RV pro-apoptotic Bax-to-Bcl2 ratio and RV and LV apoptotic rates, which were prevented by tacrolimus. BD induced increased expression of the pro-inflammatory IL-6-to-IL-10 ratio, their related receptors, and vascular cell adhesion molecule-1 in both the RV and LV. These changes were prevented by tacrolimus. RV and LV neutrophil infiltration induced by BD was partly prevented by tacrolimus. BD was associated with decreased RV expression of the β-1 adrenergic receptor and sarcomere (myosin heavy chain [MYH]7-to-MYH6 ratio) components, while β-3 adrenergic receptor, nitric oxide-synthase 3, and glucose transporter 1 expression increased. These changes were prevented by tacrolimus. Conclusions: Brain death was associated with isolated RV dysfunction. Tacrolimus prevented RV dysfunction induced by BD through the inhibition of apoptosis and inflammation activation. Full article

(This article belongs to the Special Issue Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity)

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23 pages, 6169 KiB

Open AccessArticle

Inflammatory Cytokines That Enhance Antigen Responsiveness of Naïve CD8⁺ T Lymphocytes Modulate Chromatin Accessibility of Genes Impacted by Antigen Stimulation

by Akouavi Julite Irmine Quenum, Madanraj Appiya Santharam, Sheela Ramanathan and Subburaj Ilangumaran

Int. J. Mol. Sci. 2022, 23(22), 14122; https://doi.org/10.3390/ijms232214122 - 16 Nov 2022

Cited by 1 | Viewed by 1880

Abstract

Naïve CD8⁺ T lymphocytes exposed to certain inflammatory cytokines undergo proliferation and display increased sensitivity to antigens. Such ‘cytokine priming’ can promote the activation of potentially autoreactive and antitumor CD8⁺ T cells by weak tissue antigens and tumor antigens. To elucidate the molecular mechanisms of cytokine priming, naïve PMEL-1 TCR transgenic CD8⁺ T lymphocytes were stimulated with IL-15 and IL-21, and chromatin accessibility was assessed using the assay for transposase-accessible chromatin (ATAC) sequencing. PMEL-1 cells stimulated by the cognate antigenic peptide mgp100_25-33 served as controls. Cytokine-primed cells showed a limited number of opening and closing chromatin accessibility peaks compared to antigen-stimulated cells. However, the ATACseq peaks in cytokine-primed cells substantially overlapped with those of antigen-stimulated cells and mapped to several genes implicated in T cell signaling, activation, effector differentiation, negative regulation and exhaustion. Nonetheless, the expression of most of these genes was remarkably different between cytokine-primed and antigen-stimulated cells. In addition, cytokine priming impacted the expression of several genes following antigen stimulation in a synergistic or antagonistic manner. Our findings indicate that chromatin accessibility changes in cytokine-primed naïve CD8⁺ T cells not only underlie their increased antigen responsiveness but may also enhance their functional fitness by reducing exhaustion without compromising regulatory controls. Full article

(This article belongs to the Special Issue Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity)

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10 pages, 1099 KiB

Open AccessArticle

Imaging Memory T-Cells Stratifies Response to Adjuvant Metformin Combined with αPD-1 Therapy

by Julian L. Goggi, Siddesh V. Hartimath, Shivashankar Khanapur, Boominathan Ramasamy, Zan Feng Chin, Peter Cheng, Hui Xian Chin, You Yi Hwang and Edward G. Robins

Int. J. Mol. Sci. 2022, 23(21), 12892; https://doi.org/10.3390/ijms232112892 - 25 Oct 2022

Cited by 1 | Viewed by 1558

Abstract

The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [¹⁸F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting K_V1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [¹⁸F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells. Full article

(This article belongs to the Special Issue Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity)

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Review

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29 pages, 2251 KiB

Open AccessReview

Involvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases

by Julie Sarrand and Muhammad S. Soyfoo

Int. J. Mol. Sci. 2023, 24(19), 14481; https://doi.org/10.3390/ijms241914481 - 23 Sep 2023

Cited by 2 | Viewed by 2225

Abstract

Epithelial-mesenchymal transition (EMT) is a complex reversible biological process characterized by the loss of epithelial features and the acquisition of mesenchymal features. EMT was initially described in developmental processes and was further associated with pathological conditions including metastatic cascade arising in neoplastic progression and organ fibrosis. Fibrosis is delineated by an excessive number of myofibroblasts, resulting in exuberant production of extracellular matrix (ECM) proteins, thereby compromising organ function and ultimately leading to its failure. It is now well acknowledged that a significant number of myofibroblasts result from the conversion of epithelial cells via EMT. Over the past two decades, evidence has accrued linking fibrosis to many chronic autoimmune and inflammatory diseases, including systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), and inflammatory bowel diseases (IBD). In addition, chronic inflammatory states observed in most autoimmune and inflammatory diseases can act as a potent trigger of EMT, leading to the development of a pathological fibrotic state. In the present review, we aim to describe the current state of knowledge regarding the contribution of EMT to the pathophysiological processes of various rheumatic conditions. Full article

(This article belongs to the Special Issue Mechanisms and Means of Immune Modulation in Innate and Adaptive Immunity)

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