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Analysis of the immunoglobulin kappa gene reveals that multiple elements are responsible for full hypermutation. Removal of a few elements significantly affects but does not abolish the process. The experiments using transgenic mice reveal that substitution of the V-kappa promoter by a beta-globin promoter does not suppress hypermutation. This suggests the absence of specific signals in the V-Kappa promoter.

Pregnancy poses a conundrum for the immune systems of placental mammals. A pregnant female's immune system has to defend both mother and fetus from pathogens, while at the same time [...]

The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3’s function. Subdomains within this key region link Foxp3 to several independent mechanisms of transcriptional regulation. Our study suggests that Foxp3, even in the absence of its DNA-binding forkhead domain, acts as a bridge between DNA-binding interaction partners and proteins with effector function permitting it to regulate a large number of genes. We show that, in one such mechanism, Foxp3 recruits class I histone deacetylases to the promoters of target genes, counteracting activation-induced histone acetylation and thereby suppressing their expression. [ABSTRACT FROM AUTHOR]

Background: CD4+ T cells are key regulators of the adaptive immune system and can be divided into T helper (Th) cells and regulatory T (Treg) cells. During an immune response Th cells mature from a naive state into one of several effector subtypes that exhibit distinct functions. The transcriptional mechanisms that underlie the specific functional identity of CD4+ T cells are not fully understood. Results: To assist investigations into the transcriptional identity and regulatory processes of these cells we performed mRNA-sequencing on three murine T helper subtypes (Th1, Th2 and Th17) as well as on splenic Treg cells and induced Treg (iTreg) cells. Our integrated analysis of this dataset revealed the gene expression changes associated with these related but distinct cellular identities. Each cell subtype differentially expresses a wealth of 'subtype upregulated' genes, some of which are well known whilst others promise new insights into signalling processes and transcriptional regulation. We show that hundreds of genes are regulated purely by alternative splicing to extend our knowledge of the role of post-transcriptional regulation in cell differentiation. Conclusions: This CD4+ transcriptome atlas provides a valuable resource for the study of CD4+ T cell populations. To facilitate its use by others, we have made the data available in an easily accessible online resource at www.th-express.org. [ABSTRACT FROM AUTHOR]

Regulatory T cells play an essential role in preventing fetal rejection by the maternal immune system. Here we show that, based on the expression of CCR5, regulatory T cells can be divided into a highly suppressive CCR5+ and a far less suppressive CCRS- sub-population, suggesting that the former represent the effector arm of regulatory T cells. Although regulatory T ceils from CCR5-/- gene deletion mutants still suppress, they are less effective mediators of maternal-fetal tolerance. The accumulation of CCR5+ regulatory T cells at this site appears to be enhanced by alloantigen. This finding is in stark contrast to the systemic expansion of regulatory T cells during pregnancy, which appears to be alloantigen-independent. The fact that CCR5+ regulatory T cells preferentially accumulate in the gravid uterus and that expression of CCR5 on regulatory T cells can be induced by activation lead us to propose that CCR5 is responsible for the accumulation of those regulatory T cells that have been activated by paternal antigens. [ABSTRACT FROM AUTHOR]

The Olf-1/EBF (O/E) family of transcription factors plays important roles in neural development and B-cell maturation. We have utilized a variation of the direct selection scheme (Degenerate Oligo-based Direct Selection, or DODS) to identify a fourth member of the O/E family (O/E-4). We demonstrated that, similar to previously identified mouse O/E proteins, O/E-4 is expressed in the neuronal and basal cell layers of mouse olfactory epithelium. However, unlike other O/E members, O/E-4 expression is absent in the vomeronasal organ. O/E-4 can partner with the other O/Es to form heterodimers that are capable of binding an Olf-1 consensus site in vitro. In contrast to other O/E family members, the O/E-4 protein only weakly activates transcription in a reporter assay. In summary, we have identified O/E-4 utilizing a novel homology screening method. Our results suggest that O/E-4 may interact with other O/E family members to regulate gene expression in the olfactory sensory neurons. Key Words: Olf-1; EBF; olfactory; VNO; transcription; direct selection; homology screening. [Copyright &y& Elsevier]

The immune system has the ability to suppress undesirable responses, such as those against commensal bacteria, food, and paternal antigens in placenta pregnancy. The lineage-specific transcription factor Foxp3 orchestrates the development and function of regulatory T cells underlying this immunological tolerance. Despite the crucial role of Foxp3 in supporting immune homeostasis, little is known about its origin, evolution, and species conservation. We explore these questions using comparative genomics, structural modeling, and functional analyses. Our data reveal that key gain-of-function events occurred during the evolution of Foxp3 in higher vertebrates. We identify key conserved residues in its forkhead domain and show a detailed analysis of the N-terminal region of Foxp3, which is only conserved in mammals. These components are under purifying selection, and our mutational analyses demonstrate that they are essential for Foxp3 function. Our study points to critical functional adaptations in immune tolerance among higher vertebrates, and suggests that Foxp3-mediated transcriptional mechanisms emerged during mammalian evolution as a stepwise gain of functional domains that enabled Foxp3 to interact with a multitude of interaction partners., Organismic and Evolutionary Biology

Expression of the lineage-specific DNA-binding factor Foxp3 controls the development and function of naturally occurring regulatory T cells. Foxp3 has been shown to interact with a multitude of transcriptional regulators including NFAT, NF-\(\kappa\)B (p65), Runx1 and ROR\(\lambda\)t, as well as the histone modification enzymes TIP60, HDAC7 and HDAC9. The sum of these interactions is believed to cause the change in the transcriptional program of regulatory T cells. Here we show that Foxp3 directly or as part of a multimeric complex engages with the NF-\(\kappa\)B component c-Rel. We demonstrate that the N-terminal region of Foxp3 is required for the binding of c-Rel, but not NFAT. Conversely, deletion of the forkhead domain causes a loss of interaction with NFAT, but not c-Rel. Our findings are of particular interest, as c-Rel is crucial for the induction of Foxp3 in regulatory T cells during thymic development, but has to be repressed in mature regulatory T cells to maintain their suppressive phenotype., Organismic and Evolutionary Biology