Article

Expression of relB is required for the development of thymic medulla and dendritic cells

Biogen Inc., Cambridge, Massachusetts 02142.
Nature (Impact Factor: 42.35). 03/1995; 373(6514):531-6. DOI: 10.1038/373531a0
Source: PubMed

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.

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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 [36]. Additionally, NF-jB is a necessary element in the cell cycle, and therefore is essential for cell survival [7] [9] [16]. 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. "
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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. "
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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). "
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