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14 pages, 3122 KiB

Open AccessArticle

Acute Downregulation but Not Genetic Ablation of Murine MCU Impairs Suppressive Capacity of Regulatory CD4 T Cells

by Priska Jost, Franziska Klein, Benjamin Brand, Vanessa Wahl, Amanda Wyatt, Daniela Yildiz, Ulrich Boehm, Barbara A. Niemeyer, Martin Vaeth and Dalia Alansary

Int. J. Mol. Sci. 2023, 24(9), 7772; https://doi.org/10.3390/ijms24097772 - 24 Apr 2023

Cited by 1 | Viewed by 1896

Abstract

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca²⁺ homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca²⁺ uniporter (MCU) is the pore-forming unit in the main protein [...] Read more.

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca²⁺ homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca²⁺ uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca²⁺ uptake. Recently, MCU has been shown to modulate Ca²⁺ signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulation-specific effects remain elusive. However, mice with germline or tissue-specific ablation of Mcu did not show impaired T cell responses in vitro or in vivo, indicating that ‘chronic’ loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca²⁺ uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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18 pages, 2630 KiB

Open AccessArticle

Healthy-like CD4⁺ Regulatory and CD4⁺ Conventional T-Cell Receptor Repertoires Predict Protection from GVHD Following Donor Lymphocyte Infusion

by Jessica Schneider, Leonie Kuhlmann, Yankai Xiao, Solaiman Raha, Günter Bernhardt, Michael Stadler, Felicitas Thol, Michael Heuser, Matthias Eder, Arnold Ganser, Sarina Ravens, Reinhold Förster, Immo Prinz, Christian Koenecke and Christian R. Schultze-Florey

Int. J. Mol. Sci. 2022, 23(18), 10914; https://doi.org/10.3390/ijms231810914 - 18 Sep 2022

Cited by 3 | Viewed by 2110

Abstract

Donor lymphocyte infusion (DLI) can (re-)induce durable remission in relapsing patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). However, DLI harbors the risk of increased non-relapse mortality due to the co-occurrence of graft-versus-host disease (GVHD). GVHD onset may be caused or accompanied by changes [...] Read more.

Donor lymphocyte infusion (DLI) can (re-)induce durable remission in relapsing patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). However, DLI harbors the risk of increased non-relapse mortality due to the co-occurrence of graft-versus-host disease (GVHD). GVHD onset may be caused or accompanied by changes in the clonal T-cell receptor (TCR) repertoire. To investigate this, we analyzed T cells in a cohort of 21 patients receiving DLI after alloHSCT. We performed deep T-cell receptor β (TRB) sequencing of sorted CD4⁺CD25⁺CD127^low regulatory T cells (T_reg cells) and CD4⁺ conventional T cells (T_con cells) in order to track longitudinal changes in the TCR repertoire. GVHD following DLI was associated with less diverse but clonally expanded CD4⁺CD25⁺CD127^low T_reg and CD4⁺ T_con TCR repertoires, while patients without GVHD exhibited healthy-like repertoire properties. Moreover, the diversification of the repertoires upon GVHD treatment was linked to steroid-sensitive GVHD, whereas decreased diversity was observed in steroid-refractory GVHD. Finally, the unbiased sample analysis revealed that the healthy-like attributes of the CD4⁺CD25⁺CD127^low T_reg TCR repertoire were associated with reduced GVHD incidence. In conclusion, CD4⁺CD25⁺CD127^low T_reg and CD4⁺ T_con TRB repertoire dynamics may provide a helpful real-time tool to improve the diagnosis and monitoring of treatment in GVHD following DLI. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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13 pages, 2206 KiB

Open AccessArticle

Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series

by Christian Baumeier, Ganna Aleshcheva, Dominik Harms, Ulrich Gross, Christian Hamm, Birgit Assmus, Ralf Westenfeld, Malte Kelm, Spyros Rammos, Philip Wenzel, Thomas Münzel, Albrecht Elsässer, Mudather Gailani, Christian Perings, Alae Bourakkadi, Markus Flesch, Tibor Kempf, Johann Bauersachs, Felicitas Escher and Heinz-Peter Schultheiss

Int. J. Mol. Sci. 2022, 23(13), 6940; https://doi.org/10.3390/ijms23136940 - 22 Jun 2022

Cited by 40 | Viewed by 99167

Abstract

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case [...] Read more.

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case reports investigated potential relationships, endomyocardial biopsy (EMB)-proven cases are limited. Here, we present a comprehensive histopathological analysis of EMBs from 15 patients with reduced ejection fraction (LVEF = 30 (14–39)%) and the clinical suspicion of myocarditis following vaccination with Comirnaty^® (Pfizer-BioNTech) (n = 11), Vaxzevria^® (AstraZenica) (n = 2) and Janssen^® (Johnson & Johnson) (n = 2). Immunohistochemical EMB analyses reveal myocardial inflammation in 14 of 15 patients, with the histopathological diagnosis of active myocarditis according the Dallas criteria (n = 2), severe giant cell myocarditis (n = 2) and inflammatory cardiomyopathy (n = 10). Importantly, infectious causes have been excluded in all patients. The SARS-CoV-2 spike protein has been detected sparsely on cardiomyocytes of nine patients, and differential analysis of inflammatory markers such as CD4⁺ and CD8⁺ T cells suggests that the inflammatory response triggered by the vaccine may be of autoimmunological origin. Although a definitive causal relationship between COVID-19 vaccination and the occurrence of myocardial inflammation cannot be demonstrated in this study, data suggest a temporal connection. The expression of SARS-CoV-2 spike protein within the heart and the dominance of CD4⁺ lymphocytic infiltrates indicate an autoimmunological response to the vaccination. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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14 pages, 1620 KiB

Open AccessArticle

The Mandible Ameliorates Facial Allograft Rejection and Is Associated with the Development of Regulatory T Cells and Mixed Chimerism

by Dante De Paz, Ana Elena Aviña, Esteban Cardona, Chin-Ming Lee, Chia-Hsien Lin, Cheng-Hung Lin, Fu-Chan Wei and Aline Yen Ling Wang

Int. J. Mol. Sci. 2021, 22(20), 11104; https://doi.org/10.3390/ijms222011104 - 14 Oct 2021

Cited by 3 | Viewed by 2624

Abstract

Vascularized composite allografts contain various tissue components and possess relative antigenicity, eliciting different degrees of alloimmune responses. To investigate the strategies for achieving facial allograft tolerance, we established a mouse hemiface transplant model, including the skin, muscle, mandible, mucosa, and vessels. However, the [...] Read more.

Vascularized composite allografts contain various tissue components and possess relative antigenicity, eliciting different degrees of alloimmune responses. To investigate the strategies for achieving facial allograft tolerance, we established a mouse hemiface transplant model, including the skin, muscle, mandible, mucosa, and vessels. However, the immunomodulatory effects of the mandible on facial allografts remain unclear. To understand the effects of the mandible on facial allograft survival, we compared the diversities of different facial allograft-elicited alloimmunity between a facial osteomyocutaneous allograft (OMC), including skin, muscle, oral mucosa, and vessels, and especially the mandible, and a myocutaneous allograft (MC) including the skin, muscle, oral mucosa, and vessels, but not the mandible. The different facial allografts of a BALB/c donor were transplanted into a heterotopic neck defect on fully major histocompatibility complex-mismatched C57BL/6 mice. The allogeneic OMC (Allo-OMC) group exhibited significant prolongation of facial allograft survival compared to the allogeneic MC group, both in the presence and absence of FK506 immunosuppressive drugs. With the use of FK506 monotherapy (2 mg/kg) for 21 days, the allo-OMC group, including the mandible, showed prolongation of facial allograft survival of up to 65 days, whereas the myocutaneous allograft, without the mandible, only survived for 34 days. The Allo-OMC group also displayed decreased lymphocyte infiltration into the facial allograft. Both groups showed similar percentages of B cells, T cells, natural killer cells, macrophages, and dendritic cells in the blood, spleen, and lymph nodes. However, a decrease in pro-inflammatory T helper 1 cells and an increase in anti-inflammatory regulatory T cells were observed in the blood and lymph nodes of the Allo-OMC group. Significantly increased percentages of donor immune cells were also observed in three lymphoid organs of the Allo-OMC group, suggesting mixed chimerism induction. These results indicated that the mandible has the potential to induce anti-inflammatory effects and mixed chimerism for prolonging facial allograft survival. The immunomodulatory understanding of the mandible could contribute to reducing the use of immunosuppressive regimens in clinical face allotransplantation including the mandible. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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Review

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18 pages, 1043 KiB

Open AccessReview

Autoreactive T-Cells in Psoriasis: Are They Spoiled Tregs and Can Therapies Restore Their Functions?

by Immacolata Pietraforte and Loredana Frasca

Int. J. Mol. Sci. 2023, 24(5), 4348; https://doi.org/10.3390/ijms24054348 - 22 Feb 2023

Cited by 7 | Viewed by 4931

Abstract

Psoriasis is a chronic inflammatory skin disease, which affects 2–4% of the population worldwide. T-cell derived factors such as Th17 and Th1 cytokines or cytokines such as IL-23, which favors Th17-expansion/differentiation, dominate in the disease. Therapies targeting these factors have been developed over [...] Read more.

Psoriasis is a chronic inflammatory skin disease, which affects 2–4% of the population worldwide. T-cell derived factors such as Th17 and Th1 cytokines or cytokines such as IL-23, which favors Th17-expansion/differentiation, dominate in the disease. Therapies targeting these factors have been developed over the years. An autoimmune component is present, as autoreactive T-cells specific for keratins, the antimicrobial peptide LL37 and ADAMTSL5 have been described. Both autoreactive CD4 and CD8 T-cells exist, produce pathogenic cytokines, and correlate with disease activity. Along with the assumption that psoriasis is a T-cell-driven disease, Tregs have been studied extensively over the years, both in the skin and in circulation. This narrative review resumes the main findings about Tregs in psoriasis. We discuss how Tregs increase in psoriasis but are impaired in their regulatory/suppressive function. We debate the possibility that Tregs convert into T-effector cells under inflammatory conditions; for instance, they may turn into Th17-cells. We put particular emphasis on therapies that seem to counteract this conversion. We have enriched this review with an experimental section analyzing T-cells specific for the autoantigen LL37 in a healthy subject, suggesting that a shared specificity may exist between Tregs and autoreactive responder T-cells. This suggests that successful psoriasis treatments may, among other effects, restore Tregs numbers and functions. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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21 pages, 1180 KiB

Open AccessReview

Treg Therapy for the Induction of Immune Tolerance in Transplantation—Not Lost in Translation?

by Nina Pilat, Romy Steiner and Jonathan Sprent

Int. J. Mol. Sci. 2023, 24(2), 1752; https://doi.org/10.3390/ijms24021752 - 16 Jan 2023

Cited by 9 | Viewed by 5595

Abstract

The clinical success of solid organ transplantation is still limited by the insufficiency of immunosuppressive regimens to control chronic rejection and late graft loss. Moreover, serious side effects caused by chronic immunosuppressive treatment increase morbidity and mortality in transplant patients. Regulatory T cells [...] Read more.

The clinical success of solid organ transplantation is still limited by the insufficiency of immunosuppressive regimens to control chronic rejection and late graft loss. Moreover, serious side effects caused by chronic immunosuppressive treatment increase morbidity and mortality in transplant patients. Regulatory T cells (Tregs) have proven to be efficient in the induction of allograft tolerance and prolongation of graft survival in numerous preclinical models, and treatment has now moved to the clinics. The results of the first Treg-based clinical trials seem promising, proving the feasibility and safety of Treg therapy in clinical organ transplantation. However, many questions regarding Treg phenotype, optimum dosage, antigen-specificity, adjunct immunosuppressants and efficacy remain open. This review summarizes the results of the first Treg-based clinical trials for tolerance induction in solid organ transplantation and recapitulates what we have learnt so far and which questions need to be resolved before Treg therapy can become part of daily clinical practice. In addition, we discuss new strategies being developed for induction of donor-specific tolerance in solid organ transplantation with the clinical aims of prolonged graft survival and minimization of immunosuppression. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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20 pages, 846 KiB

Open AccessReview

Human Regulatory T Cells: Understanding the Role of Tregs in Select Autoimmune Skin Diseases and Post-Transplant Nonmelanoma Skin Cancers

by Nicole Chizara Oparaugo, Kelsey Ouyang, Nam Phuong N. Nguyen, Amanda M. Nelson and George W. Agak

Int. J. Mol. Sci. 2023, 24(2), 1527; https://doi.org/10.3390/ijms24021527 - 12 Jan 2023

Cited by 11 | Viewed by 6629

Abstract

Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under [...] Read more.

Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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13 pages, 6139 KiB

Open AccessReview

Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes

by Angela M. Mitchell and Aaron W. Michels

Int. J. Mol. Sci. 2022, 23(6), 3155; https://doi.org/10.3390/ijms23063155 - 15 Mar 2022

Cited by 9 | Viewed by 3733

Abstract

While progress has been made toward understanding mechanisms that lead to the development of autoimmunity, there is less knowledge regarding protective mechanisms from developing such diseases. For example, in type 1 diabetes (T1D), the immune-mediated form of diabetes, the role of pathogenic T [...] Read more.

While progress has been made toward understanding mechanisms that lead to the development of autoimmunity, there is less knowledge regarding protective mechanisms from developing such diseases. For example, in type 1 diabetes (T1D), the immune-mediated form of diabetes, the role of pathogenic T cells in the destruction of pancreatic islets is well characterized, but immune-mediated mechanisms that contribute to T1D protection have not been fully elucidated. One potential protective mechanism includes the suppression of immune responses by regulatory CD4 T cells (Tregs) that recognize self-peptides from islets presented by human leukocyte antigen (HLA) class II molecules. In this review, we summarize what is known about the antigenic self-peptides recognized by Tregs in the context of T1D. Full article

(This article belongs to the Special Issue T-regulatory Cells in Autoimmunity and Transplantation)

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