Regulatory T cells (T
) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8
T cells. To better understand the mechanisms involved, we used ex vivo ...three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from T
-depleted mice were cultured in this system. Experiments with neutralizing antibodies showed that blocking transforming growth factor-β (TGF-β) also prevented immunosuppression. Immunosuppression depended on cell-cell contact or cellular proximity because soluble factors from the collagen-fibrin gel cultures did not inhibit tumor cell killing by T cells. Moreover, intravital, two-photon microscopy showed that tumor-specific Pmel-1 effector T cells physically interacted with tumor-resident T
in mice. T
isolated from B16 tumors alone were sufficient to suppress CD8
T cell-mediated killing, which depended on surface-bound TGF-β on the T
Immunosuppression of CD8
T cells correlated with a decrease in the abundance of the cytolytic protein granzyme B and an increase in the cell surface amount of the immune checkpoint receptor programmed cell death protein 1 (PD-1). These findings suggest that contact between T
and antitumor T cells in the tumor microenvironment inhibits antimelanoma immunity in a TGF-β-dependent manner and highlight potential ways to inhibit intratumoral T
therapeutically.
The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed ...cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8⁺ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8⁺ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of integrative cancer immunotherapies that sculpt the tumor microenvironment to promote definitive tumor rejection.
Standardizing scavenger receptor nomenclature Prabhudas, Mercy; Bowdish, Dawn; Drickamer, Kurt ...
The Journal of immunology (1950),
2014-Mar-01, 2014-03-01, 20140301, Letnik:
192, Številka:
5
Journal Article
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Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid ...cells and recognize a variety of ligands, including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the U.S. National Institute of Allergy and Infectious Diseases, National Institutes of Health to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of non-self or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. The discussion and nomenclature recommendations described in this report only refer to mammalian scavenger receptors. The purpose of this article is to describe the proposed mammalian nomenclature and classification developed at the workshop and to solicit additional feedback from the broader research community.
The goal of the HIBEAM/NNBAR program is to search for baryon number violation via the conversion or oscillation of neutrons into sterile neutrons and/or antineutrons at the European Spallation ...Source. A key experimental component of the program is the construction of an annihilation detector to directly observe the production of an antineutron following the oscillation. Design studies for the annihilation detector are presented. The predicted response of the detector models are studied using Geant4 simulations made with Monte Carlo simulations of the annihilation signal topology and cosmic ray backgrounds. Particle identification and sensitive discriminating observables, such as invariant mass and sphericity, are shown.
Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes ...in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.
Aquatic ecosystems are major sources of greenhouse gases (GHG). Representative measurements of GHG fluxes from aquatic ecosystems to the atmosphere are vital for quantitative understanding of ...relationships between biogeochemistry and climate. Fluxes occur at high temporal variability at diel or longer scales, which are not captured by traditional short-term deployments (often in the order of 30 min) of floating flux chambers. High temporal frequency measurements are necessary but also extremely labor intensive if manual flux chamber based methods are used. Therefore, we designed an inexpensive and easily mobile automated flux chamber (AFC) for extended deployments. The AFC was designed to measure in situ accumulation of gas in the chamber and also to collect gas samples in an array of sample bottles for subsequent analysis in the laboratory, providing two independent ways of CH4 concentration measurements. We here present the AFC design and function together with data from initial laboratory tests and from a field deployment.
We describe a quantitative model for assessing the cytolytic activity of antigen-specific CD8+ T cells in vitro and in vivo in which the concentration of antigen-specific CD8+ T cells determines the ...efficiency with which these cells kill cognate antigen-expressing melanoma cells in packed cell pellets, in three-dimensional collagen-fibrin gels in vitro, and in established melanomas in vivo. In combination with a clonogenic assay for melanoma cells, collagen-fibrin gels are 4,500-5,500-fold more sensitive than the packed cell pellet-type assays generally used to measure CD8+ T cell cytolytic activity. An equation previously used to describe neutrophil bactericidal activity in vitro and in vivo also describes antigen-specific CD8+ T cell-mediated cytolysis of cognate antigen-expressing melanoma cells in collagen-fibrin gels in vitro and in transplanted tumors in vivo. We have used this equation to calculate the critical concentration of antigen-specific CD8+ T cells, which is the concentration of these cells required to hold constant the concentration of a growing population of cognate antigen-expressing melanoma cells. It is approximately 3.5x10(5)/ml collagen-fibrin gel in vitro and approximately 3x10(6)/ml or /g melanoma for previously published studies of ex vivo-activated adoptively transferred tumor antigen-specific CD8+ T cell killing of cognate antigen-expressing melanoma cells in established tumors in vivo. The antigen-specific CD8+ T cell concentration required to kill 100% of 2x10(7)/ml cognate antigen-expressing melanoma cells in collagen fibrin gels is >or=10(7)/ml of gel.
The NNBAR experiment for the European Spallation Source will search for free neutrons converting to antineutrons with an expected sensitivity improvement of three orders of magnitude compared to the ...last such search. This paper describes both the simulations of a key component for the experiment, the neutron optical reflector and the expected gains in sensitivity.
Aquatic ecosystems are major sources of greenhouse gases
(GHGs). Robust measurements of natural GHG emissions are vital for evaluating
regional to global carbon budgets and for assessing climate ...feedbacks of
natural emissions to improve climate models. Diffusive and ebullitive
(bubble) transport are two major pathways of gas release from surface
waters. To capture the high temporal variability of these fluxes in a
well-defined footprint, we designed and built an inexpensive device that
includes an easily mobile diffusive flux chamber and a bubble counter all
in one. In addition to automatically collecting gas samples for subsequent
various analyses in the laboratory, this device also utilized a low-cost
carbon dioxide (CO2) sensor (SenseAir, Sweden) and methane (CH4)
sensor (Figaro, Japan) to measure GHG fluxes. Each of the devices was
equipped with an XBee module to enable local radio communication (DigiMesh
network) for time synchronization and data readout at a server controller
station on the lakeshore. The software of this server controller was operated on
a low-cost computer (Raspberry Pi), which has a 3G connection for remote
control and monitor functions from anywhere in the world. This study shows
the potential of a low-cost automatic sensor network system for studying GHG
fluxes on lakes in remote locations.
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