scholarly journals Multiple sclerosis-associated changes in the composition and immune functions of spore-forming bacteria

2018 ◽  
Author(s):  
Egle Cekanaviciute ◽  
Anne-Katrin Pröbstel ◽  
Anna Thomann ◽  
Tessel F. Runia ◽  
Patrizia Casaccia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Lymphocytes ◽  
Microbial Communities ◽  
Immune Functions ◽  
Simple Description ◽  
Regulatory T Lymphocytes ◽  
Select Group ◽  
Spore Forming Bacteria

AbstractMultiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa and show that their presence correlates with impaired differentiation of IL-10 secreting, regulatory T lymphocytes in-vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of pro-inflammatory, IFNγ+ T lymphocytes. However, when fed into antibiotic-treated mice, both MS and control derived spore-forming bacteria were able to induce immunoregulatory responses.Our analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth.ImportanceDespite the rapid emergence of microbiome related studies in human diseases, few go beyond a simple description of relative taxa levels in a select group of patients. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of both complete microbial communities and individual taxa, revealing novel functional associations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is associated with impaired immunomodulatory responses in vitro.

scholarly journals Multiple Sclerosis-Associated Changes in the Composition and Immune Functions of Spore-Forming Bacteria

mSystems ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Egle Cekanaviciute ◽  
Anne-Katrin Pröbstel ◽  
Anna Thomann ◽  
Tessel F. Runia ◽  
Patrizia Casaccia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Lymphocytes ◽  
Microbial Communities ◽  
Immune Functions ◽  
Content Type ◽  
Physiological Importance ◽  
The Impact ◽  
Spore Forming Bacteria

ABSTRACT Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria, which primarily belong to the classes Bacilli and Clostridia in the phylum Firmicutes, have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa (primarily in the class Clostridia) and show that their presence correlates with impaired differentiation of IL-10-secreting, regulatory T lymphocytes in vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of proinflammatory, IFN-γ+ T lymphocytes. However, when fed into antibiotic-treated mice, both MS and control-derived spore-forming bacteria were able to induce similar IL-10-expressing Treg immunoregulatory responses, thus ameliorating symptoms of experimental allergic encephalomyelitis (EAE). Our analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth. IMPORTANCE To address the impact of microbiome on disease development, it is essential to go beyond a descriptive study and evaluate the physiological importance of microbiome changes. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of spore-forming microbial communities, revealing novel functional correlations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform-resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is correlated with impaired immunomodulatory responses in vitro.

scholarly journals Kv1.3 Channel Up-Regulation in Peripheral Blood T Lymphocytes of Patients With Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ioannis Markakis ◽  
Ioannis Charitakis ◽  
Christine Beeton ◽  
Melpomeni Galani ◽  
Elpida Repousi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Calcium Influx ◽  
Lymphocyte Function ◽  
Kv1.3 Channel ◽  
Kv1.3 Channels

Voltage-gated Kv1.3 potassium channels are key regulators of T lymphocyte activation, proliferation and cytokine production, by providing the necessary membrane hyper-polarization for calcium influx following immune stimulation. It is noteworthy that an accumulating body of in vivo and in vitro evidence links these channels to multiple sclerosis pathophysiology. Here we studied the electrophysiological properties and the transcriptional and translational expression of T lymphocyte Kv1.3 channels in multiple sclerosis, by combining patch clamp recordings, reverse transcription polymerase chain reaction and flow cytometry on freshly isolated peripheral blood T lymphocytes from two patient cohorts with multiple sclerosis, as well as from healthy and disease controls. Our data demonstrate that T lymphocytes in MS, manifest a significant up-regulation of Kv1.3 mRNA, Kv1.3 membrane protein and Kv1.3 current density and therefore of functional membrane channel protein, compared to control groups (p < 0.001). Interestingly, patient sub-grouping shows that Kv1.3 channel density is significantly higher in secondary progressive, compared to relapsing-remitting multiple sclerosis (p < 0.001). Taking into account the tight connection between Kv1.3 channel activity and calcium-dependent processes, our data predict and could partly explain the reported alterations of T lymphocyte function in multiple sclerosis, while they highlight Kv1.3 channels as potential therapeutic targets and peripheral biomarkers for the disease.

Absence of CCR4 Enhances the Function of Expanded Regulatory T-Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2172-2172
Author(s):  
James M. Coghill ◽  
Hans Seidel ◽  
Jonathan S. Serody
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Critical Role ◽  
Cell Transplant ◽  
Similar Frequency ◽  
Regulatory T Lymphocytes ◽  
Treg Function

Abstract Chemokine Receptor 4 (CCR4) has been shown to be important for the homing of effector T-lymphocytes (Teffs) to cutaneous and possibly pulmonary sites of inflammation. CCR4 is also expressed on the surface of regulatory T-lymphocytes (Tregs), and previous work has suggested a critical role for CCR4 for their in-vivo suppressive ability. Since the skin and lung are important sites of graft-versus-host disease (GVHD) morbidity, we set out to determine the contribution of CCR4 to both Teff and Treg function in a murine stem-cell transplant model. Methods: C57BL/6 (B6) mice served as bone marrow (BM) donors, and B6xDBA/2 F1 (B6D2) mice functioned as recipients. Teffs and Tregs were obtained from wild-type (WT) or CCR4 knockout (CCR4−/−) B6 mice. For Teff studies, recipient animals were lethally irradiated and administered T-cell depleted (TCD) BM cells +/− splenic Teffs from WT or CCR4−/− donors. For Treg studies, mice received TCD BM + WT Teffs +/− naive or expanded Tregs from WT or CCR4−/− donors. Results: Animals receiving WT or CCR4−/− Teffs all developed severe GVHD with an 88% mortality rate. Using flow cytometry, we demonstrated that WT and CCR4−/− eGFP+ Teffs were able to accumulate in the skin and lungs of recipient animals at a similar frequency, suggesting a non-essential role for CCR4 in Teff homing to these sites. Attention was next directed towards the influence of CCR4 on Treg function in-vivo. Those animals receiving BM and Teffs without Tregs developed aggressive GVHD with 100% mortality. In contrast, when animals were administered BM and naïve Tregs from either WT or CCR4−/− donors two days prior to receiving Teffs, all animals demonstrated 100% survival and only mild GVHD, suggesting a non-obligatory role for CCR4 for Treg function in-vivo. Since CCR4 is upregulated on Tregs and Teffs after activation, we next examined whether its absence would exert a greater effect on the ability of expanded Tregs to protect against GVHD in-vivo compared to naïve cells. Animals were irradiated and received TCD BM plus Teffs +/− Tregs from WT or CCR4−/− donors previously expanded in-vitro. Those animals receiving BM and Teffs without Tregs all developed severe GVHD with 100% mortality. Ex-vivo expanded WT Tregs, 80% of which expressed L-selectin at low levels, provided only marginal GVHD protection with 12.5% survival when given concurrently with Teffs at a 1:1 ratio. In contrast, expanded CCR4−/− Tregs provided superior in-vivo GVHD protection, with 50% of mice surviving long term (see figure, p=.05 for WT versus CCR4−/− Treg groups). This enhanced protection in-vivo occurred despite an inferior ability of expanded CCR4−/− Tregs to inhibit T-cell proliferation in an in-vitro mixed lymphocyte reaction compared to WT cells. Migration studies did not reveal a difference in the trafficking of expanded CCR4−/− Tregs compared to WT cells except for a greater frequency of CCR4−/− Tregs in the mesenteric lymph node on day +7. Conclusions: Our data suggest that naïve CCR4−/− Tregs are as efficient as WT cells in preventing GVHD, and that CCR4 is not required for the induction of GVHD by Teffs. Paradoxically we show that expanded Tregs function better to prevent GVHD in the absence of CCR4. Current work is underway to determine the mechanism for this finding. Figure Figure

scholarly journals DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation

2019 ◽  
Vol 116 (18) ◽  
pp. 8985-8994 ◽  
Author(s):  
Massimo Costanza ◽  
Pietro L. Poliani ◽  
Paola Portararo ◽  
Barbara Cappetti ◽  
Silvia Musio ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Sterile Inflammation ◽  
Autoimmune Encephalomyelitis ◽  
Priming Phase ◽  
The Central Nervous System

The extrusion of DNA traps contributes to a key mechanism in which innate immune cells clear pathogens or induce sterile inflammation. Here we provide evidence that CD4+ T cells, a critical regulator of adaptive immunity, release extracellular threads of DNA on activation. These DNA extrusions convey autocrine costimulatory signals to T lymphocytes and can be detected in lymph nodes isolated during the priming phase of experimental autoimmune encephalomyelitis (EAE), a CD4+ T cell-driven mouse model of multiple sclerosis. Pharmacologic inhibition of mitochondrial reactive oxygen species (mtROS) abolishes the extrusion of DNA by CD4+ T cells, reducing cytokine production in vitro and T cell priming against myelin in vivo. Moreover, mtROS blockade during established EAE markedly ameliorates disease severity, dampening autoimmune inflammation of the central nervous system. Taken together, these experimental results elucidate a mechanism of intrinsic immune costimulation mediated by DNA threads released by activated T helper cells, and identify a potential therapeutic target for such disorders as multiple sclerosis, neuromyelitis optica, and CD4+ T cell-mediated disorders.

scholarly journals Synergistic effects of CTLA-4 blockade with tremelimumab and elimination of regulatory T lymphocytes in vitro and in vivo

2010 ◽  
Vol 129 (2) ◽  
pp. 374-386 ◽  
Author(s):  
Natalia Suarez ◽  
Carlos Alfaro ◽  
Juan Dubrot ◽  
Asis Palazon ◽  
Elixabet Bolaños ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Synergistic Effects ◽  
Regulatory T Lymphocytes

scholarly journals A high proportion of T lymphocytes that infiltrate H-2-incompatible heart allografts in vivo express genes encoding cytotoxic cell-specific serine proteases, but do not express the MEL-14-defined lymph node homing receptor.

1988 ◽  
Vol 167 (3) ◽  
pp. 1124-1136 ◽  
Author(s):  
C Mueller ◽  
H K Gershenfeld ◽  
C G Lobe ◽  
C Y Okada ◽  
R C Bleackley ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Allograft Rejection ◽  
Killer Cell ◽  
Cdna Clones ◽  
Immune Functions ◽  
Serine Esterase ◽  
Cytolytic Cell

The role of cytotoxic cells in in vivo immune functions such as allograft rejection is unknown. To begin to assess the function of cytolytic cells in vivo we have begun with cytolytic cell-specific functional molecules: we have isolated and characterized cytolytic cell-specific cDNA clones from cytolytic T cell clones, both encoding distinct serine esterases. The HF gene encodes a trypsin-like enzyme while the C11 gene encodes an enzyme with likely specificity for acidic residues. Here we demonstrate, using in situ hybridization with RNA probe, that both genes are expressed selectively in a subset of T lymphocytes that have infiltrated cardiac allografts. The phenotype of these cells is consistent with the most frequent phenotype of active CTL raised in vitro: they are predominantly CD4-, CD8+, MEL-14- T cell blasts. Thus the expression of these genes, each of which encodes serine esterase found in killer cell granules in vitro, is a valid marker for these cells in vivo as well. The kinetics of their accumulation is consistent with, but not proof of, a putative role in allograft rejection. It is likely that HF and C11 gene expression will be of diagnostic value.

scholarly journals Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4216-4221 ◽  
Author(s):  
Olivier Joffre ◽  
Nathalie Gorsse ◽  
Paola Romagnoli ◽  
Denis Hudrisier ◽  
Joost P. M. van Meerwijk
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Third Party ◽  
Antigen Specificity ◽  
Minor Histocompatibility Antigens ◽  
Regulatory T Lymphocytes

Abstract Thymus-derived regulatory T lymphocytes of CD4+CD25+ phenotype regulate a large variety of beneficial and deleterious immune responses and can inhibit lethal graft-versus-host disease in rodents. In vitro, CD4+CD25+ T cells require specific major histocompatibility complex (MHC)/peptide ligands for their activation, but once activated they act in an antigen-nonspecific manner. In vivo, regulatory T cells are also activated in an antigen-specific fashion, but nothing is known about antigen specificity of their suppressor-effector function. Here we show that CD4+CD25+ regulatory T lymphocytes isolated from naive mice and activated in vitro with allogeneic antigen-presenting cells (APCs) induced specific long-term tolerance to bone marrow grafts disparate for major and minor histocompatibility antigens; whereas “target” bone marrow was protected, third-party bone marrow was rejected. Importantly, in mice injected with a mix of target and third-party bone marrows, protection and rejection processes took place simultaneously. These results indicate that CD4+CD25+ regulatory T cells can act in an antigen-specific manner in vivo. Our results suggest that CD4+CD25+ regulatory T cells could in the future be used in clinical settings to induce specific immunosuppression. (Blood. 2004;103:4216-4221)

scholarly journals Generalizing game-changing species across microbial communities

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Jie Deng ◽  
Marco Tulio Angulo ◽  
Serguei Saavedra
Keyword(s):  
Microbial Communities ◽  
Context Dependency ◽  
Heuristic Rules ◽  
Resident Species ◽  
Experimental Systems ◽  
Environment And Health ◽  
Structuralist Theory ◽  
Context Specific

AbstractMicrobes form multispecies communities that play essential roles in our environment and health. Not surprisingly, there is an increasing need for understanding if certain invader species will modify a given microbial community, producing either a desired or undesired change in the observed collection of resident species. However, the complex interactions that species can establish between each other and the diverse external factors underlying their dynamics have made constructing such understanding context-specific. Here we integrate tractable theoretical systems with tractable experimental systems to find general conditions under which non-resident species can change the collection of resident communities—game-changing species. We show that non-resident colonizers are more likely to be game-changers than transients, whereas game-changers are more likely to suppress than to promote resident species. Importantly, we find general heuristic rules for game-changers under controlled environments by integrating mutual invasibility theory with in vitro experimental systems, and general heuristic rules under changing environments by integrating structuralist theory with in vivo experimental systems. Despite the strong context-dependency of microbial communities, our work shows that under an appropriate integration of tractable theoretical and experimental systems, it is possible to unveil regularities that can then be potentially extended to understand the behavior of complex natural communities.

scholarly journals Design of a multi-epitope vaccine against cervical cancer using immunoinformatics approaches

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samira Sanami ◽  
Fatemeh Azadegan-Dehkordi ◽  
Mahmoud Rafieian-Kopaei ◽  
Majid Salehi ◽  
Maryam Ghasemi-Dehnoo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Lymphocytes ◽  
Tertiary Structure ◽  
Therapeutic Vaccine ◽  
Epitope Prediction ◽  
Therapeutic Effects ◽  
Epitope Vaccine ◽  
In Vivo Experiments

AbstractCervical cancer, caused by human papillomavirus (HPV), is the fourth most common type of cancer among women worldwide. While HPV prophylactic vaccines are available, they have no therapeutic effects and do not clear up existing infections. This study aims to design a therapeutic vaccine against cervical cancer using reverse vaccinology. In this study, the E6 and E7 oncoproteins from HPV16 were chosen as the target antigens for epitope prediction. Cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) epitopes were predicted, and the best epitopes were selected based on antigenicity, allergenicity, and toxicity. The final vaccine construct was composed of the selected epitopes, along with the appropriate adjuvant and linkers. The multi-epitope vaccine was evaluated in terms of physicochemical properties, antigenicity, and allergenicity. The tertiary structure of the vaccine construct was predicted. Furthermore, several analyses were also carried out, including molecular docking, molecular dynamics (MD) simulation, and in silico cloning of the vaccine construct. The results showed that the final proposed vaccine could be considered an effective therapeutic vaccine for HPV; however, in vitro and in vivo experiments are required to validate the efficacy of this vaccine candidate.

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