The T cell STAT signaling network is reprogrammed within hours of bacteremia via secondary signals.

The delicate balance between protective immunity and inflammatory disease is challenged during sepsis, a pathologic state characterized by aspects of both a hyperactive immune response and immunosuppression. The events driven by systemic infection by bacterial pathogens on the T cell signaling network that likely control these responses have not been illustrated in great detail. We characterized how intracellular signaling within the immune compartment is reprogrammed at the single cell level when the host is challenged with a high level of pathogen. To accomplish this, we applied flow cytometry to measure the phosphorylation potential of key signal transduction proteins during acute bacterial challenge. We modeled the onset of sepsis by i.v. administration of avirulent strains of Listeria monocytogenes and Escherichia coli to mice. Within 6 h of bacterial challenge, T cells were globally restricted in their ability to respond to specific cytokine stimulations as determined by assessing the extent of STAT protein phosphorylation. Mechanisms by which this negative feedback response occurred included SOCS1 and SOCS3 gene up-regulation and IL-6-induced endocystosis of the IL-6 receptor. Additionally, macrophages were partially tolerized in their ability to respond to TLR agonists. Thus, in contrast to the view that there is a wholesale immune activation during sepsis, one immediate host response to blood-borne bacteria was induction of a refractory period during which leukocyte activation by specific stimulations was attenuated.

Targeting the A2AR in cancer; early lessons from the clinic.

The immunosuppressive tumor microenvironment (TME) represents a challenge that all immunotherapies must overcome to enable a robust and durable anti-tumor response. One of the dominant mechanisms of immunosuppression in the TME is hypoxia and the generation of extracellular adenosine [1]. Pioneering work from Drs Ohta and Sitkovsky demonstrating that adenosine signaling through the adenosine 2A receptor (A2AR) inhibits T cells has led to the development of several agents designed to inhibit the production or downstream signaling of adenosine [2••,3••]. This review will focus on the safety, efficacy, and biomarkers associated with A2AR antagonists in clinical development.

Coordinate actions of innate immune responses oppose those of the adaptive immune system during Salmonella infection of mice.

The immune system enacts a coordinated response when faced with complex environmental and pathogenic perturbations. We used the heterogeneous responses of mice to persistent Salmonella infection to model system-wide coordination of the immune response to bacterial burden. We hypothesized that the variability in outcomes of bacterial growth and immune response across genetically identical mice could be used to identify immune elements that serve as integrators enabling co-regulation and interconnectedness of the innate and adaptive immune systems. Correlation analysis of immune response variation to Salmonella infection linked bacterial load with at least four discrete, interacting functional immune response "cassettes." One of these, the innate cassette, in the chronically infected mice included features of the innate immune system, systemic neutrophilia, and high serum concentrations of the proinflammatory cytokine interleukin-6. Compared with mice with a moderate bacterial load, mice with the highest bacterial burden exhibited high activity of this innate cassette, which was associated with a dampened activity of the adaptive T cell cassette-with fewer plasma cells and CD4(+) T helper 1 cells and increased numbers of regulatory T cells-and with a dampened activity of the cytokine signaling cassette. System-wide manipulation of neutrophil numbers revealed that neutrophils regulated signal transducer and activator of transcription (STAT) signaling in B cells during infection. Thus, a network-level approach demonstrated unappreciated interconnections that balanced innate and adaptive immune responses during the dynamic course of disease and identified signals associated with pathogen transmission status, as well as a regulatory role for neutrophils in cytokine signaling.

IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system.

Immune cells function in an interacting hierarchy that coordinates the activities of various cell types according to genetic and environmental contexts. We developed graphical approaches to construct an extensible immune reference map from mass cytometry data of cells from different organs, incorporating landmark cell populations as flags on the map to compare cells from distinct samples. The maps recapitulated canonical cellular phenotypes and revealed reproducible, tissue-specific deviations. The approach revealed influences of genetic variation and circadian rhythms on immune system structure, enabled direct comparisons of murine and human blood cell phenotypes, and even enabled archival fluorescence-based flow cytometry data to be mapped onto the reference framework. This foundational reference map provides a working definition of systemic immune organization to which new data can be integrated to reveal deviations driven by genetics, environment, or pathology.