scholarly journals Monocytes in Neonatal Bacterial Sepsis: Think Tank or Workhorse?

BioChem ◽  
2022 ◽  
Vol 2 (1) ◽  
pp. 27-43
Author(s):  
Caitlin Doughty ◽  
Louise Oppermann ◽  
Niels-Ulrik Hartmann ◽  
Stephan Dreschers ◽  
Christian Gille ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Bacterial Infections ◽  
Cell Activation ◽  
Viral Infections ◽  
Organ Damage ◽  
Host Responses ◽  
Critical Event ◽  
Think Tank ◽  
Inflammatory Reactions ◽  
Inflammatory Conditions

Infection and sepsis remain among the leading causes of neonatal mortality. The susceptibility of newborns to infection can be attributed to their immature immune system. Regarding immune response, monocytes represent a numerically minor population of leukocytes. However, they contribute to a variety of immunological demands, such as continuous replenishment of resident macrophages under non-infectious conditions and migration to inflamed sites where they neutralize pathogens and secrete cytokines. Further functions include the presentation of antigens and T-cell activation. Cytokines coordinate host responses to bacterial and viral infections and orchestrate ongoing physiological signaling between cells of non-immune tissues. A critical event is the skewing of the cytokine repertoire to achieve a resolution of infection. In this regard, monocytes may hold a key position as deciders in addition to their phagocytic activity, securing the extinction of pathogens to prevent broader organ damage by toxins and pro-inflammatory reactions. Neonatal monocytes undergo various regulatory and metabolic changes. Thus, they are thought to be vulnerable in anticipating pro-inflammatory conditions and cause severe progressions which increase the risk of developing sepsis. Furthermore, clinical studies have shown that exposure to inflammation puts neonates at a high risk for adverse pulmonary, immunological and other organ developments, which may result in multiorgan disease. This review discusses significant functions and impairments of neonatal monocytes that are decisive for the outcome of bacterial infections.

scholarly journals Pitavastatin Exerts Potent Anti-Inflammatory and Immunomodulatory Effects via the Suppression of AP-1 Signal Transduction in Human T Cells

2019 ◽  
Vol 20 (14) ◽  
pp. 3534 ◽  
Author(s):  
Liv Weichien Chen ◽  
Chin-Sheng Lin ◽  
Min-Chien Tsai ◽  
Shao-Fu Shih ◽  
Zhu Wei Lim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mitogen Activated Protein Kinase ◽  
Lipid Lowering ◽  
Enzyme Linked Immunosorbent Assay ◽  
Atherosclerotic Cardiovascular Disease ◽  
Immunomodulatory Effects ◽  
Inflammatory Reactions ◽  
Human T Cells

Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on T cell activation. This study evaluated the immunomodulatory capacities of three common statins, pitavastatin, atorvastatin, and rosuvastatin, in activated human T cells. The enzyme-linked immunosorbent assay (ELISA) and quantitative real time polymerase chain reaction (qRT-PCR) results demonstrated stronger inhibitory effects of pitavastatin on the cytokine production of T cells activated by phorbol 12-myristate 13-acetate (PMA) plus ionomycin, including interleukin (IL)-2, interferon (IFN)-γ, IL-6, and tumor necrosis factor α (TNF-α). Molecular investigations revealed that pitavastatin reduced both activating protein-1 (AP-1) DNA binding and transcriptional activities. Further exploration showed the selectively inhibitory effect of pitavastatin on the signaling pathways of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Our findings suggested that pitavastatin might provide additional benefits for treating hypercholesterolemia and ASCVD through its potent immunomodulatory effects on the suppression of ERK/p38/AP-1 signaling in human T cells.

T cell-T cell activation in multiple sclerosis

1997 ◽  
Vol 3 (4) ◽  
pp. 238-242 ◽  
Author(s):  
JW Lindsey ◽  
RH Kerman ◽  
JS Wolinsky
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Activated T Cells ◽  
In Vitro Proliferation

Activated T cells are able to stimulate proliferation in resting T cells through an antigen non-specific mechanism. The in vivo usefulness of this T cell-T cell activation is unclear, but it may serve to amplify immune responses. T cell-T cell activation could be involved in the well-documented occurrence of multiple sclerosis (MS) exacerbations following viral infections. Excessive activation via this pathway could also be a factor in the etiology of MS. We tested the hypothesis that excessive T cell-T cell activation occurs in MS patients using in vitro proliferation assays comparing T cells from MS patients to T cells from controls. When tested as responder cells, T cells from MS patients proliferated slightly less after stimulation with previously activated cells than T cells from controls. When tested as stimulator cells, activated cells from MS patients stimulated slightly more non-specific proliferation than activated cells from controls. Neither of these differences were statistically significant We conclude that T cell proliferation in response to activated T cells is similar in MS and controls.

scholarly journals In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B.

1995 ◽  
Vol 15 (3) ◽  
pp. 1294-1301 ◽  
Author(s):  
I Alkalay ◽  
A Yaron ◽  
A Hatzubai ◽  
S Jung ◽  
A Avraham ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Extended Period ◽  
Activation Process ◽  
Nf Kappa B ◽  
Inflammatory Reactions ◽  
I Kappa B Alpha ◽  
Cytoplasmic Complex ◽  
Stimulation Of

NF-kappa B is a major inducible transcription factor in many immune and inflammatory reactions. Its activation involves the dissociation of the inhibitory subunit I kappa B from cytoplasmic NF-kappa B/Rel complexes, following which the Rel proteins are translocated to the nucleus, where they bind to DNA and activate transcription. Phosphorylation of I kappa B in cell-free experiments results in its inactivation and release from the Rel complex, but in vivo NF-kappa B activation is associated with I kappa B degradation. In vivo phosphorylation of I kappa B alpha was demonstrated in several recent studies, but its role is unknown. Our study shows that the T-cell activation results in rapid phosphorylation of I kappa B alpha and that this event is a physiological one, dependent on appropriate lymphocyte costimulation. Inducible I kappa B alpha phosphorylation was abolished by several distinct NF-kappa B blocking reagents, suggesting that it plays an essential role in the activation process. However, the in vivo induction of I kappa B alpha phosphorylation did not cause the inhibitory subunit to dissociate from the Rel complex. We identified several protease inhibitors which allow phosphorylation of I kappa B alpha but prevent its degradation upon cell stimulation, presumably through inhibition of the cytoplasmic proteasome. In the presence of these inhibitors, phosphorylated I kappa B alpha remained bound to the Rel complex in the cytoplasm for an extended period of time, whereas NF-kappa B activation was abolished. It appears that activation of NF-kappa B requires degradation of I kappa B alpha while it is a part of the Rel cytoplasmic complex, with inducible phosphorylation of the inhibitory subunit influencing the rate of degradation.

scholarly journals A unified atlas of CD8 T cell dysfunctional states in cancer and infection

2020 ◽  
Author(s):  
Yuri Pritykin ◽  
Joris van der Veeken ◽  
Allison Pine ◽  
Yi Zhong ◽  
Merve Sahin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Bacterial Infections ◽  
Cell Activation ◽  
Cell Loss ◽  
Cd8 T Cell ◽  
Cell Immunity ◽  
Allele Specific ◽  
T Cell Dysfunction

ABSTRACTCD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across different experimental and clinical settings. By carrying out a unified analysis of over 300 ATAC-seq and RNA-seq experiments from twelve independent studies of CD8 T cell dysfunction in cancer and infection we defined a shared differentiation trajectory towards terminal dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell activation states across models. Experimental dissection of acute and chronic viral infection using scATAC-seq and allele-specific scRNA-seq identified state-specific transcription factors and captured the early emergence of highly similar TCF1+ progenitor-like populations at an early branch point, at which epigenetic features of functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.

scholarly journals Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Guillaume Harlé ◽  
Camille Kowalski ◽  
Juan Dubrot ◽  
Dale Brighouse ◽  
Gaëlle Clavel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphatic Endothelial Cells ◽  
Inflammatory Conditions ◽  
Sphingosine 1 Phosphate ◽  
Tissue Antigens ◽  
Important Regulator ◽  
T Cell Survival

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.

scholarly journals Mechanosensing through YAP controls T cell activation and metabolism

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Kevin P. Meng ◽  
Fatemeh S. Majedi ◽  
Timothy J. Thauland ◽  
Manish J. Butte
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Autoimmune Diabetes ◽  
Tissue Mechanics ◽  
Effector T Cells ◽  
Metabolic Reprogramming ◽  
Dependent Manner

Upon immunogenic challenge, lymph nodes become mechanically stiff as immune cells activate and proliferate within their encapsulated environments, and with resolution, they reestablish a soft baseline state. Here we show that sensing these mechanical changes in the microenvironment requires the mechanosensor YAP. YAP is induced upon activation and suppresses metabolic reprogramming of effector T cells. Unlike in other cell types in which YAP promotes proliferation, YAP in T cells suppresses proliferation in a stiffness-dependent manner by directly restricting the translocation of NFAT1 into the nucleus. YAP slows T cell responses in systemic viral infections and retards effector T cells in autoimmune diabetes. Our work reveals a paradigm whereby tissue mechanics fine-tune adaptive immune responses in health and disease.

Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation

2013 ◽  
Vol 305 (12) ◽  
pp. H1761-H1771 ◽  
Author(s):  
Ryo Watanabe ◽  
Ryoko Wakizono Azuma ◽  
Jun-ichi Suzuki ◽  
Masahito Ogawa ◽  
Akiko Itai ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Weight Ratio ◽  
Heart Weight ◽  
Autoimmune Myocarditis ◽  
Inflammatory Reactions ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg−1·day−1) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.

scholarly journals Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection

2012 ◽  
Vol 209 (10) ◽  
pp. 1769-1779 ◽  
Author(s):  
Sarah Enouz ◽  
Lucie Carrié ◽  
Doron Merkler ◽  
Michael J. Bevan ◽  
Dietmar Zehn
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Negative Selection ◽  
Cell Activation ◽  
Organ Damage ◽  
Peptide Ligands ◽  
Peripheral Tolerance ◽  
High Avidity ◽  
Transgenic Cells

Central and peripheral tolerance prevent autoimmunity by deleting the most aggressive CD8+ T cells but they spare cells that react weakly to tissue-restricted antigen (TRA). To reveal the functional characteristics of these spared cells, we generated a transgenic mouse expressing the TCR of a TRA-specific T cell that had escaped negative selection. Interestingly, the isolated TCR matches the affinity/avidity threshold for negatively selecting T cells, and when developing transgenic cells are exposed to their TRA in the thymus, only a fraction of them are eliminated but significant numbers enter the periphery. In contrast to high avidity cells, low avidity T cells persist in the antigen-positive periphery with no signs of anergy, unresponsiveness, or prior activation. Upon activation during an infection they cause autoimmunity and form memory cells. Unexpectedly, peptide ligands that are weaker in stimulating the transgenic T cells than the thymic threshold ligand also induce profound activation in the periphery. Thus, the peripheral T cell activation threshold during an infection is below that of negative selection for TRA. These results demonstrate the existence of a level of self-reactivity to TRA to which the thymus confers no protection and illustrate that organ damage can occur without genetic predisposition to autoimmunity.

scholarly journals CD169 Defines Activated CD14+ Monocytes With Enhanced CD8+ T Cell Activation Capacity

2021 ◽  
Vol 12 ◽  
Author(s):  
Alsya J. Affandi ◽  
Katarzyna Olesek ◽  
Joanna Grabowska ◽  
Maarten K. Nijen Twilhaar ◽  
Ernesto Rodríguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Type I ◽  
Inflammatory Conditions ◽  
Activated Monocytes ◽  
And Function

Monocytes are antigen-presenting cells (APCs) that play diverse roles in promoting or regulating inflammatory responses, but their role in T cell stimulation is not well defined. In inflammatory conditions, monocytes frequently show increased expression of CD169/Siglec-1, a type-I interferon (IFN-I)-regulated protein. However, little is known about the phenotype and function of these CD169+ monocytes. Here, we have investigated the phenotype of human CD169+ monocytes in different diseases, their capacity to activate CD8+ T cells, and the potential for a targeted-vaccination approach. Using spectral flow cytometry, we detected CD169 expression by CD14+ CD16- classical and CD14+ CD16+ intermediate monocytes and unbiased analysis showed that they were distinct from dendritic cells, including the recently described CD14-expressing DC3. CD169+ monocytes expressed higher levels of co-stimulatory and HLA molecules, suggesting an increased activation state. IFNα treatment highly upregulated CD169 expression on CD14+ monocytes and boosted their capacity to cross-present antigen to CD8+ T cells. Furthermore, we observed CD169+ monocytes in virally-infected patients, including in the blood and bronchoalveolar lavage fluid of COVID-19 patients, as well as in the blood of patients with different types of cancers. Finally, we evaluated two CD169-targeting nanovaccine platforms, antibody-based and liposome-based, and we showed that CD169+ monocytes efficiently presented tumor-associated peptides gp100 and WT1 to antigen-specific CD8+ T cells. In conclusion, our data indicate that CD169+ monocytes are activated monocytes with enhanced CD8+ T cell stimulatory capacity and that they emerge as an interesting target in nanovaccine strategies, because of their presence in health and different diseases.

scholarly journals Activation of T Lymphocytes in Response to Persistent Bacterial Infection: Induction of CD11b and of Toll-Like Receptors on T Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Dimitra Kotsougiani ◽  
Marco Pioch ◽  
Birgit Prior ◽  
Volkmar Heppert ◽  
G. Maria Hänsch ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Bacterial Infection ◽  
T Cell Activation ◽  
Bacterial Infections ◽  
Cell Activation ◽  
Polymorphonuclear Neutrophils ◽  
Virus Infections ◽  
Toll Like Receptors ◽  
Phagocytic Cells

T cell activation is invariably associated with virus infections, but activation of T cells is also noted, for example, in patients with persistent bacterial infections with intracellular pathogens or localised bacterial biofilms. The latter is characterised by a destructive inflammatory process. Massive infiltration of leukocytes, predominantly of polymorphonuclear neutrophils (PMNs) and of T lymphocytes, is seen. While PMN influx into sites of bacterial infection is in line with their role as “first-line defence” a role of T cells in bacterial infection has not yet been delineated. We now found evidence for activation and expansion of peripheral blood T cells and an upregulation of Toll-like receptors 1, 2, and 4 on small portions of T cells. T cells recovered from the infected site were terminally differentiated and produced interferon gamma, a cytokine known to enhance functions of phagocytic cells, leading to the conclusion that infiltrated T cells support the local immuner defence.

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