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The T Cell STAT Signaling Network Is Reprogrammed within Hours of Bacteremia via Secondary Signals¹

Andrew N. Hotson^*, Jonathan W. Hardy^2,*,, Matthew B. Hale^2,*, Christopher H. Contag^*, and Garry P. Nolan^3,*

^* Department of Microbiology and Immunology, The Baxter Laboratory of Genetic Pharmacology, and Departments of Pediatrics and Radiology, Stanford University School of Medicine, Stanford, CA 94305

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Heart, Lung, and Blood Institute Contract N01-HV-28183 and National Institutes of Health Grant HHSN272200700038C. M.B.H. was supported by a National Science Foundation predoctoral fellowship.

² J.W.H. and M.B.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Garry P. Nolan, Department of Microbiology and Immunology, The Baxter Laboratory of Genetic Pharmacology, Stanford University School of Medicine, 269 Campus Drive, CCSR 3205, Stanford, CA 94305. E-mail address: gnolan{at}stanford.edu

⁴ Abbreviations used in this paper: PAMP, pathogen associated molecular pattern; Ax, Alexa fluorophore; BMDC, bone marrow-derived dendritic cell; BMDM, bone marrow-derived macrophage; cDC, conventional DC; DC, dendritic cell; IKK, IB kinase; LLO, listeriolysin O; MAPKAPK-2, MAPK activated protein kinase-2; MFI, median fluorescence intensity; PAM3, PAM3CysSK4; pDC, plasmacytoid DC; SOCS, suppressor of cytokine signaling.