scholarly journals Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

2015 ◽  
Vol 89 (18) ◽  
pp. 9616-9630 ◽  
Author(s):  
Tianyu He ◽  
Egidio Brocca-Cofano ◽  
Delbert G. Gillespie ◽  
Cuiling Xu ◽  
Jennifer L. Stock ◽  
...  
Keyword(s):  
T Cells ◽  
Adenosine Deaminase ◽  
Immune Activation ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Proinflammatory Cytokine Production ◽  
Gut Dysfunction ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACTThe role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO.Ex vivoadministration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted.IMPORTANCEThe mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune activation/inflammation in nonprogressive SIV infections by limiting SIV-related gut inflammation. Conversely, in progressive SIV infection, significant degradation of ADO occurs, possibly due to an early increase of ADO deaminase complexing protein 2 (CD26) and adenosine deaminase. Our study supports therapeutic interventions to offset alterations of this pathway during progressive HIV/SIV infections. These potential approaches to control chronic immune activation and inflammation during pathogenic SIV infection may prevent HIV disease progression.

scholarly journals Central Role of MyD88-Dependent Dendritic Cell Maturation and Proinflammatory Cytokine Production to ControlBrucella abortusInfection

2008 ◽  
Vol 180 (2) ◽  
pp. 1080-1087 ◽  
Author(s):  
Gilson Costa Macedo ◽  
Diogo Matos Magnani ◽  
Natalia Barbosa Carvalho ◽  
Oscar Bruna-Romero ◽  
Ricardo T. Gazzinelli ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Proinflammatory Cytokine Production

Abatacept modulates proinflammatory macrophage responses upon cytokine-activated T cell and Toll-like receptor ligand stimulation

2011 ◽  
Vol 71 (1) ◽  
pp. 80-83 ◽  
Author(s):  
M H Wenink ◽  
K C M Santegoets ◽  
A M Platt ◽  
W B van den Berg ◽  
P L C M van Riel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Proinflammatory Cytokine Production ◽  
Toll Like Receptor ◽  
Activated T Cells ◽  
Activated T Cell ◽  
Ligand Stimulation

ObjectivesWe investigated whether Abatacept might reduce proinflammatory cytokine production by macrophages upon contact with cytokine activated T cells and/or stimulation with TLR ligands.MethodsMacrophages and cytokine stimulated T cells (Tck) were added together in the presence of Abatacept or a control Ig, with or without TLR ligands. The production of cytokines was determined by luminex.ResultsAbatacept reduced Tck-induced production of TNFa by macrophages. Tck and TLR ligands synergistically induced the production of proinflammatory cytokines by macrophages, especially IL-12p70. The production of IL-12p70 coincided with the production of IFNg, which were both reduced in the presence of Abatacept.ConclusionsTck induce the production of TNFa by macrophages and facilitate the highly increased production of proinflammatory cytokines in the presence of TLR ligands. Abatacept was shown to potently suppress these pathways suggesting that its role may extend beyond antigen specific T cell mediated effector function.

scholarly journals Differential Dynamics of Regulatory T-Cell and Th17 Cell Balance in Mesenteric Lymph Nodes and Blood following Early Antiretroviral Initiation during Acute Simian Immunodeficiency Virus Infection

2019 ◽  
Vol 93 (19) ◽  
Author(s):  
Alexis Yero ◽  
Omar Farnos ◽  
Henintsoa Rabezanahary ◽  
Gina Racine ◽  
Jérôme Estaquier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Immune Activation ◽  
Rhesus Macaques ◽  
Mesenteric Lymph Nodes ◽  
Tissue Fibrosis ◽  
Mesenteric Lymph ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Increased frequencies of immunosuppressive regulatory T cells (Tregs) are associated with gut lymphoid tissue fibrosis and dysfunction which, in turn, contribute to disease progression in chronic simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection. Mesenteric lymph nodes (MLNs), which drain the large and small intestine, are critical sites for the induction and maintenance of gut mucosal immunity. However, the dynamics of Tregs in MLNs are not well understood due to the lack of accessibility to these tissues in HIV-infected individuals. Here, the dynamics of Tregs in blood and MLNs were assessed in SIV-infected rhesus macaques (RMs) following early antiretroviral drug (ARV) initiation. Early ARV initiation reduced T-cell immune activation, as assessed by HLA-DR/CD39 expression, and prevented the depletion of memory CCR6+ Th17 cells in both blood and MLNs. Untreated animals showed higher frequencies of Tregs, CD39+ Tregs, thymic Tregs, and new memory CD4 populations sharing similarity with Tregs as CTLA4+ PD1– and CTLA4+ PD1– FoxP3+ T cells. Despite early ARV treatment, the frequencies of these Treg subsets remained unchanged within the MLNs and, in contrast to blood normalization, the Th17/Treg ratio remained distorted in MLNs. Furthermore, our results highlighted that the expressions of IDO-1, TGFβ1 and collagen-1 mRNA remained unchanged in MLN of ARV-treated RMs. ARV interruption did not affect T-cell immune activation and Th17/Treg ratios in MLN. Altogether, our data demonstrated that early ARV initiation within the first few days of SIV infection is unable to reduce the frequencies and homing of various subsets of Tregs within the MLNs which, in turn, may result in tissue fibrosis, impairment in MLN function, and HIV persistence. IMPORTANCE Tregs contribute to SIV/HIV disease progression by inhibition of antiviral specific responses and effector T-cell proliferation. Tregs also cause tissue fibrosis via transforming growth factor β1 production and collagen deposition, which are associated with microbial translocation and generalized immune activation. Early ARV initiation upon viral exposure is recommended globally and results in improved immune function recovery and reduced viral persistence. Here, using an acute SIV infection model of rhesus macaques, we demonstrated for the first time that despite clear improvements in mucosal CD4 T cells, in contrast to blood, Treg frequencies in MLNs remained elevated following early ARV initiation. The particular Th17/Treg balance observed in MLNs can contribute, in part, to the maintenance of mucosal fibrosis during suppressive ARV treatment. Our results provide a better understanding of gut mucosal immune dynamics following early ARV initiation. These findings suggest that Treg-based treatments could serve as a novel immunotherapeutic approach to decrease gut mucosal damage during SIV/HIV infections.

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