Durable Interactions of T Cells with T Cell Receptor Stimuli in the Absence of a Stable Immunological Synapse.

T cells engage in two modes of interaction with antigen-presenting surfaces: stable synapses and motile kinapses. Although it is surmised that durable interactions of T cells with antigen-presenting cells involve synapses, in situ 3D imaging cannot resolve the mode of interaction. We have established in vitro 2D platforms and quantitative metrics to determine cell-intrinsic modes of interaction when T cells are faced with spatially continuous or restricted stimulation.

Actin polymerization-dependent activation of Cas-L promotes immunological synapse stability.

The immunological synapse formed between a T-cell and an antigen-presenting cell is important for cell-cell communication during T-cell-mediated immune responses. Immunological synapse formation begins with stimulation of the T-cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization-dependent process.

Legacy and emerging organic pollutants in liver and plasma of long-finned pilot whales (Globicephala melas) from waters surrounding the Faroe Islands.

Concentrations of PCBs, organochlorine pesticides (OCPs), brominated flame retardants and a suite of relevant metabolites of these POPs, in all 175 different compounds, were determined in liver and plasma of traditionally hunted pilot whales (n=14 males and n=13 females of different age groups) from the Faroe Islands. The main objectives of this study were to determine differences in the presence and concentrations of the compounds in the liver and plasma, how they depend on developmental stage (calves, sub adults, and adult females), and to assess maternal transfer of the compounds to suckling calves. Generally, the lipid weight (lw) concentrations of quantified POPs in the liver and plasma of pilot whales were positively correlated, and lw concentrations of most POPs did not differ between these matrices.

Thyroid hormones and deiodinase activity in plasma and tissues in relation to high levels of organohalogen contaminants in East Greenland polar bears (Ursus maritimus).

Previous studies have shown relationships between organohalogen contaminants (OHCs) and circulating levels of thyroid hormones (THs) in arctic wildlife. However, there is a lack of knowledge concerning the possible functional effects of OHCs on TH status in target tissues for TH-dependent activity. The relationships between circulating (plasma) levels of OHCs and various TH variables in plasma as well as in liver, muscle and kidney tissues from East Greenland sub-adult polar bears (Ursus maritimus) sampled in 2011 (n=7) were therefore investigated.

The transcriptional landscape of αβ T cell differentiation.

The differentiation of αβT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes.

Identification of transcriptional regulators in the mouse immune system.

The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages.

Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation.

After infection, many factors coordinate the population expansion and differentiation of CD8+ effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8+ T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8+ effector cells.

Distinct mechanisms mediate naive and memory CD8 T-cell tolerance.

Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells.

Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation.

In response to infection, CD8(+) T cells integrate multiple signals and undergo an exponential increase in cell numbers. Simultaneously, a dynamic differentiation process occurs, resulting in the formation of short-lived effector cells (SLECs; CD127(low)KLRG1(high)) and memory precursor effector cells (CD127(high)KLRG1(low)) from an early effector cell that is CD127(low)KLRG1(low) in phenotype. CD8(+) T cell differentiation during vesicular stomatitis virus infection differed significantly than during Listeria monocytogenes infection with a substantial reduction in early effector cell differentiation into SLECs.

In situ biosensing with a surface plasmon resonance fiber grating aptasensor.

Surface plasmon resonance (SPR) biosensors prepared using optical fibers can be used as a cost-effective and relatively simple-to-implement alternative to well established biosensor platforms for monitoring biomolecular interactions in situ or possibly in vivo. The fiber biosensor presented in this study utilizes an in-fiber tilted Bragg grating to excite the SPR on the surface of the sensor over a large range of external medium refractive indices, with minimal cross-sensitivity to temperature and without compromising the structural integrity of the fiber. The label-free biorecognition scheme used demonstrates that the sensor relies on the functionalization of the gold-coated fiber with aptamers, synthetic DNA sequences that bind with high specificity to a given target.

Duration of antigen availability influences the expansion and memory differentiation of T cells.

The initial engagement of the TCR through interaction with cognate peptide-MHC is a requisite for T cell activation and confers Ag specificity. Although this is a key event in T cell activation, the duration of these interactions may affect the proliferative capacity and differentiation of the activated cells. In this study, we developed a system to evaluate the temporal requirements for antigenic stimulation during an immune response in vivo.

T cell and APC dynamics in situ control the outcome of vaccination.

The factors controlling the progression of an immune response to generation of protective memory are poorly understood. We compared the in situ and ex vivo characteristics of CD8 T cells responding to different forms of the same immunogen. Immunization with live Listeria monocytogenes, irradiated L.

Functional anatomy of T cell activation and synapse formation.

T cell activation and function require a structured engagement of antigen-presenting cells. These cell contacts are characterized by two distinct dynamics in vivo: transient contacts resulting from promigratory junctions called immunological kinapses or prolonged contacts from stable junctions called immunological synapses. Kinapses operate in the steady state to allow referencing to self-peptide-MHC (pMHC) and searching for pathogen-derived pMHC.

Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells.

The factors involved in the differentiation of memory CD4 T cells from naïve precursors are poorly understood. We developed a system to examine the effect of increased competition for antigen by CD4 T cells on the generation of memory in response to infection with a recombinant vesicular stomatitis virus. Competition was initially regulated by increasing the precursor frequency of adoptively transferred naïve T cell antigen receptor transgenic CD4 T cells.

Trend of depression and the use of psychiatric medications in U.S. Veterans with hepatitis C during interferon-based therapy.

Objectives: Interferon-based therapy in patients with HCV infection may cause new psychiatric symptoms or worsening of existing psychiatric conditions. The aim of this study was to evaluate the trend of depression, and the use and the effect of psychiatric medications during interferon therapy.

Methods: Patients with HCV were evaluated at our clinic following a standardized template to collect clinical and psychiatric data at baseline, weeks 2, 4, 8, 12, and every 6 wk thereafter.

Dynamics of blood-borne CD8 memory T cell migration in vivo.

Memory T cells are distributed throughout the body following infection, but the migratory dynamics of the memory pool in vivo is unknown. The ability of circulating microbe-specific memory T cells to populate lymphoid and nonlymphoid tissues was examined using adoptive transfer and parabiosis systems. While migration of memory CD8 T cells to lymph nodes and peritoneal cavity required G(i)-coupled receptor signaling, migration to the spleen, bone marrow, lung, and liver was independent of this pathway.