Expression of relB is required for the development of thymic medulla and dendritic cells
ABSTRACT Dendritic cells (DC) derived from bone marrow are critical in the function of the immune system, for they are the primary antigen-presenting cells in the activation of T-lymphocyte response. Their differentiation from precursor cells has not been defined at a molecular level, but recent studies have shown an association between expression of the relB subunit of the NF-kappa B complex and the presence of DC in specific regions of normal unstimulated lymphoid tissues. Here we show that relB expression also correlates with differentiation of DC in autoimmune infiltrates in situ, and that a mutation disrupting the relB gene results in mice with impaired antigen-presenting cell function, and a syndrome of excess production of granulocytes and macrophages. Thymic UEA-1+ medullary epithelial cells from normal mice show striking similarities to DC and, interestingly, these cells are also absent in relB mutant mice. Taken together, these results suggest that relB is critical in the coordinated activation of genes necessary for the differentiation of two unrelated but phenotypically similar cells (DC and thymic UEA-1+ medullary epithelial cells) and is therefore a candidate for a gene determining lineage commitment in the immune system.
- SourceAvailable from: Judith Pacheco-Yepez
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- "NF-jB is a ubiquitously expressed transcription factor that upregulates the expression by many genes of cytokines, adhesion molecules, complement factors, and a variety of immunoreceptors involved in mammalian inflammatory immune response . Additionally, NF-jB is a necessary element in the cell cycle, and therefore is essential for cell survival   . On the other hand, GRs inhibit the expression of many of the same cytokines activated by NFjB , and therefore the cytokine-induced gene expression as well. "
ABSTRACT: Estrogens and glucocorticoids have synergistic effects in the micro and macrovasculature of endothelial cells (ECs), having pro-inflammatory effects in the former and inhibiting the expression of adhesion molecules in the latter. The molecular basis of these effects in the endothelium has not yet been clarified. We postulate that the ECs of the micro- and macrovasculature have different non-genomic mechanisms that regulate levels of preexisting complexes of glucocorticoids and estrogens with their respective receptors. Since these receptors are regulated by NF-κB, their expression could be critical to the activation of a pro- or anti-inflammatory response. In the macrovasculature the synergistic effects of estrogens and glucocorticoids on ECs may be through the inhibition of NF-κB, leading to the inhibition of the expression of inflammatory molecules. It seems likely that glucocorticoid-receptor and estrogen-receptor complexes directly bind to NF-κB proteins in the macrovasculature, resulting in the inhibition of an excessive proinflammatory response. Further insights into these processes may help clarify the role of the endothelial cells of different vascular beds during the inflammatory response and chronic inflammation, and thus contribute to the design of more effective therapeutic strategies for the prevention of diseases related to inflammation, including atherosclerosis, systemic lupus erythematosus and rheumatoid arthritis.Medical Hypotheses 10/2013; 81(6). DOI:10.1016/j.mehy.2013.10.007 · 1.15 Impact Factor
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- "RelB-deficient (RelB-KO) mice (Burkly et al., 1995; Weih et al., 1995; Zuklys et al., 2000) and aly/aly mice (Miyawaki et al., 1994; Kajiura et al., 2004; Shinzawa et al., 2011), which have a dysfunctional point mutation in the gene encoding NIK, showed severe defects in the development of mTECs expressing AIRE and TSAs. Consistently, these mutant mice exhibit autoimmune phenotypes. "
ABSTRACT: Thymic epithelial cells (TECs) provide the microenvironment required for the development of T cells in the thymus. A unique property of medullary thymic epithelial cells (mTECs) is their expression of a wide range of tissue-restricted self-antigens, critically regulated by the nuclear protein AIRE, which contributes to the selection of the self-tolerant T cell repertoire, thereby suppressing the onset of autoimmune diseases. The TNF receptor family (TNFRF) protein receptor activator of NF-κB (RANK), CD40 and lymphotoxin β receptor (LtβR) regulate the development and functions of mTECs. The engagement of these receptors with their specific ligands results in the activation of the NF-κB family of transcription factors. Two NF-κB activation pathways, the classical and non-classical pathways, promote the development of mature mTECs induced by these receptors. Consistently, TNF receptor-associated factor (TRAF6), the signal transducer of the classical pathway, and NF-κB inducing kinase (NIK), the signal transducer of the non-classical pathway, are essential for the development of mature mTECs. This review summarizes the current understanding of how the signaling by the TNF receptor family controls the development and functions of mTEC.Frontiers in Immunology 09/2012; 3:278. DOI:10.3389/fimmu.2012.00278
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- "In particular, medullary thymic epithelial cells (mTECs), including those expressing the Aire gene (Bjö rses et al., 1998; Heino et al., 1999, 2000), influence negative selection in several ways (Anderson et al., 2002; Derbinski et al., 2005; Liston et al., 2003), including expression of a wide array of tissue-restricted antigens for direct and indirect antigen presentation to newly selected thymocytes (Gallegos and Bevan, 2004), and the regulation of intrathymic DC positioning via Aire-dependent XCL1 expression (Lei et al., 2011). Normal mTEC development depends on NF-kB signaling, as shown by medullary abnormalities and tolerance breakdown in mice deficient in RelB (Burkly et al., 1995; Naspetti et al., 1997), Traf6 (Akiyama et al., 2005), and Nik (Kajiura et al., 2004). Moreover, mTEC maturation requires hematopoietic cell cross-talk (Shores et al., 1991), which involves signaling through various mTEC-expressed TNF receptor superfamily (TNFRSF) members (Boehm et al., 2003; Zhu and Fu, 2008). "
ABSTRACT: The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.Immunity 03/2012; 36(3):427-37. DOI:10.1016/j.immuni.2012.01.016 · 19.75 Impact Factor