Immunity
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The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1(-/-) mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. ⋯ Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-κB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation.
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Dendritic cells (DCs) initiate and maintain adaptive T helper 2 (Th2) cell responses to inhaled allergens in asthma. Various functions like antigen uptake, migration to the draining LNs, and induction of tolerance and adaptive immunity are not equally shared by all subsets of DCs, adding considerable complexity to understanding the immunology of allergic sensitization. ⋯ Clinically relevant allergens, as well as environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells, basophils, and DCs. This review summarizes the recent progress on our understanding how DCs control Th2 cell immunity in the lung.
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In response to viral infection, naive CD8(+) T cells proliferate and differentiate into cytotoxic and cytokine-producing effector cells. Here we showed that the transcription factor Blimp-1, a crucial regulator of plasma cell differentiation, was required for CD8(+) T cells to differentiate into functional killer T cells in response to influenza virus. ⋯ Antigen-specific Blimp-1-deficient CD8(+) T cells failed to appropriately regulate the transcriptional program essential for killer T cell responses and showed impaired migration to the site of infection. This study identifies Blimp-1 as a master regulator of the terminal differentiation of CD8(+) effector T cells and uncovers a conservation of the pathways that regulate the terminal differentiation of T and B cells.
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Integrin-mediated adhesion plays a central role in T cell trafficking and activation. Genetic inactivation of the guanine nucleotide-binding (G) protein alpha-subunits Galpha(12) and Galpha(13) resulted in an increased activity of integrin leukocyte-function-antigen-1 in murine CD4(+) T cells. ⋯ Mechanistically, we show that in the absence of Galpha(12) and Galpha(13) the activity of the small GTPases Rac1 and Rap1 was increased, whereas signaling of the small GTPase RhoA was strongly reduced. Our data indicate that locally produced mediators signal through Galpha(12)- and Galpha(13)-coupled receptors to negatively regulate cell polarization and adhesiveness, thereby fine-tuning T cell trafficking, proliferation, and susceptibility toward T cell-mediated diseases.
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Granzyme A (GzmA) is considered a major proapoptotic protease. We have discovered that GzmA-induced cell death involves rapid membrane damage that depends on the synergy between micromolar concentrations of GzmA and sublytic perforin (PFN). ⋯ Moreover, murine GzmA and GzmA(+) cytotoxic T lymphocytes (CTLs) induce IL-1beta from primary mouse macrophages, and GzmA(-/-) mice resist lipopolysaccharide-induced toxicity. Thus, the granule secretory pathway plays an unexpected role in inflammation, with GzmA acting as an endogenous modulator.