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Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients...
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern-recognition receptor for a variety of endogenous and exogenous ligands. However, LOX-1 function in the host immune response is not fully understood. Here, we report that LOX-1 expressed on dendritic cells (DCs) and B cells promotes humoral responses. On B cells LOX-1 signaling upregulated CCR7, promoting cellular migration...
The NLRP3 inflammasome plays a major role in innate immune responses by activating caspase-1, resulting in secretion of interleukin-18 (IL-18) and IL-1β. Although cytosolic double-stranded RNA (dsRNA) and bacterial RNA are known to activate the NLRP3 inflammasome, the upstream sensor is unknown. We investigated the potential function of DExD/H-box RNA helicase family members (previously shown to sense...
Plasmacytoid dendritic cells (pDCs) have potential influence on innate and adaptive immune responses. In this issue of Immunity, Takagi et al. (2011) established mice lacking pDCs and explored the impact of pDC ablation in vivo.
The innate immune system detects viral infection predominantly by sensing viral nucleic acids. We report the identification of a viral sensor, consisting of RNA helicases DDX1, DDX21, and DHX36, and the adaptor molecule TRIF, by isolation and sequencing of poly I:C-binding proteins in myeloid dendritic cells (mDCs). Knockdown of each helicase or TRIF by shRNA blocked the ability of mDCs to mount type I...
Previous studies suggest that thymus produces a homogenous population of natural regulatory T (Treg) cells that express a transcriptional factor FOXP3 and control autoimmunity through a cell-contact-dependent mechanism. We found two subsets of FOXP3 + natural Treg cells defined by the expression of the costimulatory molecule ICOS in the human thymus and periphery. Whereas the ICOS + ...
The development of distinct dendritic cell (DC) subsets is regulated by cytokines. The ligand for the FMS-like tyrosine kinase 3 receptor (Flt3L) is necessary for plasmacytoid DC (pDC) and conventional DC (cDC) maturation. The cytokine GM-CSF inhibits Flt3L-driven pDC production while promoting cDC growth. We show that GM-CSF selectively utilized its signal transducer STAT5 to block Flt3L-dependent...
Dendritic cells (DCs) are a heterogenous population of bone-marrow-derived immune cells. Although all DCs share a common ability to process and present antigen to naive T cells for the initiation of an immune response, they differ in surface markers, migratory patterns, localization, and cytokine production. DCs were originally considered to be myeloid cells, but recent findings have demonstrated...
The identity of T H 2 memory cells and the mechanism regulating their maintenance during allergic inflammation remain elusive. We report that circulated human CD4 + T cells expressing the prostaglandin D2 receptor (CRTH2) are T H 2 central memory T cells, characterized by their phenotype, T H 2 cytokine production, gene-expression profile, and the ability to respond...
The origin of plasmacytoid dendritic cell precursors (pDC) has been controversial. This manuscript shows that CLP and CMP both can give rise to pDCs. pDCs derived from CMP express RAG gene products and show IgHD-J rearrangement, suggesting that pDC represent a unique lineage whose gene expression program shows substantial plasticity.
A novel sequence discovered in a computational screen appears distantly related to the p35 subunit of IL-12. This factor, which we term p19, shows no biological activity by itself; instead, it combines with the p40 subunit of IL-12 to form a novel, biologically active, composite cytokine, which we term IL-23. Activated dendritic cells secrete detectable levels of this complex. IL-23 binds to IL-12Rβ1...
Somatic hypermutation in immunoglobulin variable region genes occurs within germinal centers. Here, we describe a subset of germinal center dark zone centroblasts that express only sIgD and have accumulated up to 80 mutations per heavy chain variable region (IgV H δ gene). Over half of the hypermutated IgV H δ sequences were found to be clonally related. This level of mutation is not...
Human memory B cells that carry mutated IgV region genes were isolated from tonsils by negative selection of IgD + naive B cells and CD38 + germinal center B cells and plasma cells. They were mainly found within the intraepithelial areas, but not in the B cell follicles of human tonsils. Memory B cells but not naive B cells have the capacity to present antigen directly to T cells,...
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