Browsing by Subject "Dendritic Cells"
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Item Dendritic Cells Suppress Pathogen-Induced Inflammasome Activation to Prime Naïve T Cells(2021-05-01T05:00:00.000Z) McDaniel, Margaret Mae; van Oers, Nicolai S. C.; Pasare, Chandrashekhar; Fu, Yang-Xin; Alto, Neal; Satterthwaite, Anne B.Activation of inflammasome leads to pyroptotic cell death thereby eliminating the replicative niche of virulent pathogens, a process integral to innate immunity. While inflammasome-associated cytokines such as IL-1β and IL-18 have an established role in T cell function, whether inflammasome activation in dendritic cells (DCs) is critical for T cell priming is not clear. Here, we find that lymphoid organ resident conventional DCs (cDCs) actively suppress inflammasome activation to prevent pyroptotic cell death. This protection from inflammasome-induced cell death preserves the ability of cDCs to prime both CD4 and CD8 T cells. Transcription factors IRF8 and IRF4, in cDC1s and cDC2s respectively, mediate this suppression of inflammasome activation by limiting the expression of inflammasome-associated genes. Additionally, overexpression of either of IRF4 or IRF8 is sufficient to inhibit inflammasome activation in macrophages, cells that are normally permissive to inflammasome activation. Furthermore, we find that reduced expression of IRF8 leads to aberrant inflammasome activation in cDC1s which hampers their ability to prime CD8 T cells. These results uncover the importance as well as the molecular mechanism of inflammasome suppression in cDCs and ascribe a novel post-developmental role for IRF4 and IRF8 in cDC function.Item Hyperactive Rac1 Drives MAPK-Independent Proliferation in Melanoma by Assembly of a Mechanosensitive Dendritic Actin Network(2018-06-26) Mohan, Ashwathi; Brekken, Rolf A.; Danuser, Gaudenz; Cobb, Melanie H.; Alto, NealCancer cells use a variety of mechanisms to subvert growth regulation and overcome environmental challenges. Often, these same mechanisms enable cancer cells to develop resistance to targeted therapies. Here, we describe how a hyperactivating mutation of the Rac1 GTPase (Rac1P29S) harnesses Rac1's function as a regulator of actin polymer assembly to sustain cell cycle progression in growth limiting conditions. This proliferative advantage supports metastatic colonization of melanoma cells and confers insensitivity to inhibitors of the mitogen-activated protein kinase (MAPK) pathway, a frequent target for melanoma treatment. Rac1P29S bypasses the MAPK axis through a mechanism that necessitates cell-matrix attachment, however, does not depend on integrin-mediated focal adhesion assembly and focal adhesion kinase signaling. Even without involvement of canonical adhesion signaling, cells carrying the Rac1P29S mutation show elevated traction upon drug treatment and require mechanical resistance from their surrounding matrix to gain a proliferative advantage. We describe an alternative arm for cell mechanosensing, whereby actin polymerization against a matrix of minimal rigidity organizes biochemical cues to drive proliferative signals. Hyperactivation of Rac1 by the P29S mutation channels this pathway in melanoma through Arp 2/3-dependent formation of a constrained actin brush network that results in the inactivation of tumor suppressor NF2/Merlin. These data suggest an alternative mechanism for mechanosensitive growth regulation that can be hijacked by cancer cells to circumvent the adverse conditions of foreign microenvironments or drug treatment.Item [Southwestern News](2005-09-06) Rian, RussellItem [Southwestern News](2001-12-28) Echeverria, Ione