T-Cell Activation Differentially Mediates the Host Response to Sepsis

Kasten, Kevin R.; Tschöp, Johannes; Goetzman, Holly S.; England, Lisa G.; Dattilo, Jonathan R.; Cave, Cindy M.; Seitz, Amy E.; Hildeman, David A.; Caldwell, Charles C.

doi:10.1097/shk.0b013e3181dc0845

Cited by 31 publications

(45 citation statements)

References 43 publications

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“…The suggestion of early cross talk between the innate and adaptive immune responses extends from recent reports, indicating the necessity of T cells in bacterial clearance following infection (29,37,54,55). Additionally, T-cell activation was newly linked to bacterial clearance through increased neutrophil oxidative burst and phagocytosis (29).…”

mentioning

confidence: 63%

Interleukin-7 (IL-7) Treatment Accelerates Neutrophil Recruitment through γδ T-Cell IL-17 Production in a Murine Model of Sepsis

et al. 2010

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The sepsis syndrome represents an improper immune response to infection and is associated with unacceptably high rates of mortality and morbidity. The interactions between T cells and the innate immune system while combating sepsis are poorly understood. In this report, we observed that treatment with the potent, antiapoptotic cytokine interleukin-7 (IL-7) accelerated neutrophil recruitment and improved bacterial clearance. We first determined that T cells were necessary for the previously observed IL-7-mediated enhanced survival. Next, IL-7 increased Bcl-2 expression in T cells isolated from septic mice as early as 3 h following treatment. This treatment resulted in increased gamma interferon (IFN-␥) and IP-10 production within the septic peritoneum together with local and systemic increases of IL-17 in IL-7-treated mice. We further demonstrate that the increase in IL-17 was largely due to increased recruitment and production by ␥␦ T cells, which express CXCR3. Consistent with increased IL-17 production, IL-7 treatment increased CXCL1/KC production, neutrophil recruitment, and bacterial clearance. Significantly, end-organ tissue injury was not significantly different between vehicle-and IL-7-treated mice. Collectively, these data illustrate that IL-7 can mediate the cross talk between Th1 and Th17 lymphocytes during sepsis such that neutrophil recruitment and bacterial clearance is improved while early tissue injury is not increased. All together, these observations may underlay novel potential therapeutic targets to improve the host immune response to sepsis.

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confidence: 63%

Interleukin-7 (IL-7) Treatment Accelerates Neutrophil Recruitment through γδ T-Cell IL-17 Production in a Murine Model of Sepsis

et al. 2010

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“…It is also argued that this epitope also bears at least one B cell epitope (323)(324)(325)(326)(327)(328)(329)(330)(331)(332)(333)(334)(335)(336)(337)(338)(339), however, there is only one study that has mentioned the presence of the B cell epitope [327]. In a study by Sun et al, it was shown that 50% of the B cell response generated by the OVA protein was antibody specific to the OVA323-339 epitope [327].…”

Section: Immunisation By Mannosylated Peptides Resulted In An Impairementioning

confidence: 99%

“…In a study by Sun et al, it was shown that 50% of the B cell response generated by the OVA protein was antibody specific to the OVA323-339 epitope [327]. As the vaccine structures (G1-6) contain the CD4 epitope (OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339], the in vivo ability of vaccine structures (G1-9) for a T cell activation proliferation was assessed. Here, OT-II proliferating cells are considered to be activated when T cells expressing CD45.2 increase in percentage over the total parental CD4 + T cells [329].…”

Section: Immunisation By Mannosylated Peptides Resulted In An Impairementioning

confidence: 99%

“…The antigen dependant pathway occurs when the T cell receptor binds to antigens presented by MHC molecules [323]. The antigen-independent pathway, however, is a cytokine dependant pathway [326].…”

Section: In Vivo Cd4 T-cell Proliferation/activationmentioning

confidence: 99%

“…The OVA protein naturally exists as a glycoprotein, however, it was discovered that the OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] and OVA 1-10 sequences of the OVA protein bore a B cell epitope that was capable of inducing a T cell response. This discovery was obtained by T cell mediated IgE responses that were observed against an assumed B cell epitope inside OVA323-339 and OVA1-10 peptides [185].…”

Section: Model Antigen Selectionmentioning

confidence: 99%

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Mannosylated lipopetides as model vaccines for targeting the mannose receptor

Sedaghat¹

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The mannose receptor (MR) is an important component of the immune system and understanding the structural and conformational characteristics of this receptor is a key aspect of targeted vaccine design. Improved understanding of the role of carbohydrate recognition domains (CRDs) 4-7 in recognising glycosylated ligands present on the surface of pathogens such as C. albicans, P. carinii, L. donovani, and M. tuberculosis has given new insight into MR vaccine development. Initial studies identified mannan and its derivatives to be important ligands in MR targeting, providing essential knowledge about structural properties of the MR. During the last decade many attempts have been made to target this receptor for applications including vaccine and drug development.In the present study, a library of vaccine constructs comprising fluorescently-labelled mannosylated lipid dendrimers that contained the ovalbumin CD4 + epitope, OVA323-339, as the model peptide antigen were synthesised using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in antigen presenting cells.Mannosylated building blocks were prepared with a Lewis acid reaction and the reaction was successfully modified and monitored for a better yield. This was followed by solid phase synthesis of mannosylated peptides with an azide functional group and a fluorescent tag. Considering the presence of multi-components on the designed mannosylated peptide, different methods of preparation was used and a high yield of the final mannosylated peptides with an azide functional group and a fluorescent tag were prepared. Further, OVA323-339 lipopeptides with an alkyne functional group were prepared using microwave assisted peptide synthesis. Final vaccine structures were prepared by attaching azide and alkyne functional groups using click chemistry. The same methods were applied for the preparation of a library of control vaccine structures.In vitro uptake studies performed on macrophage (F4/80 + ) and dendritic (CD11c + ) cells showed significant uptake and/or binding for vaccine constructs containing mannose and lipid, and also for the lipopeptide vaccine construct without mannose when compared to the controls (containing no lipid, no mannose and no mannose or lipid). Further, in vitro mannan competition assays demonstrated that uptake of the mannosylated and lipidated vaccine constructs was MR mediated. To address the specificity of receptor uptake, surface plasmon resonance (SPR) was performed usingBiacore technology which confirmed a high affinity of the mannosylated and lipidated vaccine constructs towards the human recombinant MR in vitro when compared with vaccine constructs without mannose. These studies also confirmed that both mannose and lipid moieties play significant II roles in receptor-mediated uptake on APCs, potentially faci...

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Genetic deletion of the HIF‐1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model

et al. 2013

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Summary Hypoxia-adenosinergic suppression and re-direction of the immune response has been implicated in the regulation of anti-pathogen and anti-tumor immunity, with Hypoxia-inducible factor 1α (HIF-1α) playing a major role. In this study, we investigated the role of isoform I.1, a quantitatively minor alternative isoform of HIF-1α, in anti-bacterial immunity and sepsis survival. By using the cecal ligation and puncture model of bacterial peritonitis we studied the function of I.1 isoform in T cells using mice with total I.1-isoform deficiency and mice with T cell-targeted I.1 knockdown. We found that genetic deletion of the I.1 isoform resulted in enhanced resistance to septic lethality, significantly reduced bacterial load in peripheral blood, increased M1 macrophage polarization, augmented levels of pro-inflammatory cytokines in serum, and significantly decreased levels of the anti-inflammatory cytokine IL-10. Our data suggest an immunosuppressive role of the I.1 isoform in T cells during bacterial sepsis that was previously unrecognized. We interpret these data as indicative that activation-inducible isoform I.1 hinders the contribution of T cells to the anti-bacterial response by affecting M1/M2 macrophage polarization and microbicidal function.

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T-Cell Activation Differentially Mediates the Host Response to Sepsis

Cited by 31 publications

References 43 publications

Interleukin-7 (IL-7) Treatment Accelerates Neutrophil Recruitment through γδ T-Cell IL-17 Production in a Murine Model of Sepsis

Interleukin-7 (IL-7) Treatment Accelerates Neutrophil Recruitment through γδ T-Cell IL-17 Production in a Murine Model of Sepsis

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

Genetic deletion of the HIF‐1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model

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