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    ABSTRACT: The subclassification of immunology into innate and adaptive immunity is challenged by innate-like T lymphocytes that use innate receptors to respond rapidly to stress despite expressing T cell antigen receptors (TCRs), a hallmark of adaptive immunity. In studies that explain how such cells can straddle innate and adaptive immunity, we found that signaling via antigen receptors, whose conventional role is to facilitate clonal T cell activation, was critical for the development of innate-like T cells but then was rapidly attenuated, which accommodated the cells' innate responsiveness. These findings permitted the identification of a previously unknown innate-like T cell subset and indicate that T cell hyporesponsiveness, a state traditionally linked to tolerance, may be fundamental to T cells entering the innate compartment and thereby providing lymphoid stress surveillance.
    No preview · Article · Nov 2013 · Nature Immunology
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    ABSTRACT: In most metazoans, all tissues contain phagocytes "in residence," generally termed "macrophages" in vertebrates. In contrast to myeloid cells produced continuously by the bone marrow (BM), tissue-resident macrophages develop during embryogenesis together with their tissue of residence, and persist in adulthood, independently of hematopoietic stem cells and the transcription factor Myb. They therefore represent an independent lineage from blood monocytes, dendritic cells, and monocytes/macrophages that are recruited to tissues during inflammation. Tissue-resident macrophage functions are yet to be completely defined. They all share the ability to scavenge toxic compounds, lipids, microorganisms, and dead cells and contribute to tissue remodeling, via phagocytosis and the production of growth factors. In contrast, the production of inflammatory mediators seems to be more associated with BM-derived cells. Tissue-resident macrophages and BM-derived myeloid cells thus differ in developmental origin and functions; the term "macrophages" could be reserved for Myb-independent-resident macrophages to avoid confusion. A genetic and molecular dissection of resident macrophage functions will reveal their roles in tissue metabolism and the maintenance of homeostasis independently of the extravasation of inflammatory leukocytes, and in the control of the recruitment of BM-derived cells in overt inflammation.
    Full-text · Article · Oct 2013 · Cold Spring Harbor Symposia on Quantitative Biology
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    ABSTRACT: Infections disturb metabolic homeostasis in many contexts, but the underlying connections are not completely understood. To address this, we use paired genetic and computational screens in Drosophila to identify transcriptional regulators of immunity and pathology and their associated target genes and physiologies. We show that Mef2 is required in the fat body for anabolic function and the immune response. Using genetic and biochemical approaches, we find that MEF2 is phosphorylated at a conserved site in healthy flies and promotes expression of lipogenic and glycogenic enzymes. Upon infection, this phosphorylation is lost, and the activity of MEF2 changes-MEF2 now associates with the TATA binding protein to bind a distinct TATA box sequence and promote antimicrobial peptide expression. The loss of phosphorylated MEF2 contributes to loss of anabolic enzyme expression in Gram-negative bacterial infection. MEF2 is thus a critical transcriptional switch in the adult fat body between metabolism and immunity.
    Full-text · Article · Sep 2013 · Cell
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