Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

Scumpia, Philip O.; Delano, Matthew J.; Kelly, Kathleen S.; O’Malley, Kerri; Efron, Philip A.; McAuliffe, Priscilla F.; Brusko, Todd M.; Ungaro, Ricardo; Barker, Tolga; Wynn, James L.; Atkinson, Mark A.; Reeves, Westley H.; Salzler, M; Moldawer, Lyle L.

doi:10.4049/jimmunol.177.11.7943

Cited by 119 publications

(123 citation statements)

References 41 publications

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“…Animal studies have documented the requirement of an intact T cell system to adequately combat a septic challenge (29,37). More recently, animal-based experiments have demonstrated that experimental septic shock is characterized by widespread T cell apoptosis and that preventing T cell apoptosis positively impacts the outcome of experimental sepsis (38)(39)(40)(41)(42)(43)(44)(45). Importantly, the concept of T cell apoptosis in human sepsis has been indirectly corroborated by autopsy studies (36,46).…”

Section: R E S E a R C H A R T I C L E M O L M Ementioning

confidence: 74%

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Shanley

Cvijanovich²,

Lin

et al. 2007

Mol Med

111

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We have conducted longitudinal studies focused on the expression profiles of signaling pathways and gene networks in children with septic shock. Genome-level expression profiles were generated from whole blood-derived RNA of children with septic shock (n = 30) corresponding to day one and day three of septic shock, respectively. Based on sequential statistical and expression filters, day one and day three of septic shock were characterized by differential regulation of 2,142 and 2,504 gene probes, respectively, relative to controls (n = 15). Venn analysis demonstrated 239 unique genes in the day one dataset, 598 unique genes in the day three dataset, and 1,906 genes common to both datasets. Functional analyses demonstrated timedependent, differential regulation of genes involved in multiple signaling pathways and gene networks primarily related to immunity and inflammation. Notably, multiple and distinct gene networks involving T cell-and MHC antigen-related biology were persistently downregulated on both day one and day three. Further analyses demonstrated large scale, persistent downregulation of genes corresponding to functional annotations related to zinc homeostasis. These data represent the largest reported cohort of patients with septic shock subjected to longitudinal genome-level expression profiling. The data further advance our genome-level understanding of pediatric septic shock and support novel hypotheses.

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Section: R E S E a R C H A R T I C L E M O L M Ementioning

confidence: 74%

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Shanley

Cvijanovich²,

Lin

et al. 2007

Mol Med

111

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“…They are increased in percentage in the peripheral blood of sepsis patients compared with that of healthy controls (46), and their number is increased in the spleen of septic mice (47). Whereas their deletion does modify the outcome of septic mice (47), their transfer improved survival in the polymicrobial model of sepsis (48) and contributed to normalize resolution of lung injury in mice exposed to LPS (49). However, they also contribute to the immunosuppressive environment associated with sepsis (50).…”

Section: Discussionmentioning

confidence: 99%

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

Souza-Fonseca-Guimarães

Parlato

Fitting

et al. 2012

The Journal of Immunology

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As sensors of infection, innate immune cells are able to recognize pathogen-associated molecular patterns by receptors such as TLRs. NK cells present in many tissues contribute to inflammatory processes, particularly through the production of IFN-γ. They may display a protective role during infection but also a detrimental role during sterile or infectious systemic inflammatory response syndrome. Nevertheless, the exact status of NK cells during bacterial sepsis and their capacity directly to respond to TLR agonists remain unclear. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors. The aim of this study was to gain insight into TLR2/TLR4/TLR9 expression on/in murine NK cells at the protein level and determine if their agonists were able to induce cytokine production. We show, by flow cytometry, a strong intracellular expression of TLR2 and a low of TLR4 in freshly isolated murine spleen NK cells, similar to that of TLR9. In vitro, purified NK cells respond to TLR2, TLR4, and TLR9 agonists, in synergy with activating cytokines (IL-2, IL-15, and/or IL-18), and produce proinflammatory cytokines (IFN-γ and GM-CSF). Finally, we explored the possible tolerance of NK cells to TLR agonists after a polymicrobial sepsis (experimental peritonitis). For the first time, to our knowledge, NK cells are shown to become tolerant in terms of proinflammatory cytokines production after sepsis. We show that this tolerance is associated with a reduction of the CD27+CD11b− subset in the spleen related to the presence of regulatory T cells and mainly mediated by TGF-β.

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“…The recruitment of innate immune effector cells is important for the containment and control of bacterial infection, as well as abscess formation and localization (7). The characteristics of the adult response to sepsis have been well described but have not been fully delineated in the neonate (6,11,18). Blood, spleen, bone marrow, and peritoneal washes were collected at multiple time points from neonates that were exposed to an LD 40 polymicrobial sepsis.…”

Section: Resultsmentioning

confidence: 99%

Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis

et al. 2011

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Previous studies have suggested that neonates rely heavily on innate immunity for their antimicrobial response to bacterial infections. However, the innate immune response by neonates to bacterial infection remains poorly characterized. Here, we show that in a murine model of neonatal polymicrobial sepsis, CXC ligand 10 (CXCL10) concentrations increase in the blood and peritoneum concordant with the peritoneal recruitment of granulocytes and macrophages. Additionally, CXC receptor 3 (CXCR3) expression on elicited peritoneal macrophages and granulocytes increases following sepsis. Blockade of CXCL10 worsens not only recruitment and phagocytic function of peritoneal granulocytes and macrophages but also survival. Deletion of CXCR3 also significantly increases mortality to a septic challenge. Finally, we demonstrate that the protective adjuvant effect of pretreatment with a Toll-like receptor 4 agonist to neonatal sepsis is dependent on an endogenous CXCL10 response and that pretreatment of neonates with CXCL10 can also significantly improve macrophage and granulocyte function and modestly improve outcome to polymicrobial sepsis. Together, these data suggest a critical role for CXCL10 signaling during neonatal sepsis.

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Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

Cited by 119 publications

References 41 publications

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis

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