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This article explores the methodological possibilities for using unverifiable, contradictory, or demonstrably false accounts of the past for historical research. Drawing from the methodological example of historical studies on accusations of vampirism in colonial East Africa, it presents histories of three Ibadi Muslim manuscript libraries on the island of Jerba, Tunisia. These stories contain contradictory or otherwise unverifiable elements, each of which raises methodological questions for its use as a historical source. The article argues that by drawing upon the methodological premise of these studies of vampires, historians can approach far more basic questions of historical research regarding chronology, contradictory evidence, and veracity. [ABSTRACT FROM AUTHOR]

SOCS3 is a cytosolic inhibitor of cytokine signaling that suppresses the activation of cytokine receptor‐associated JAK kinases. Mechanistically, SOCS3 is recruited to a site in the cytokine receptors known as the SOCS3‐interaction motif, and then binds JAK molecules to inhibit their kinase activity. The SOCS3‐interaction motif is found in receptors of the gp130 cytokine family but mostly absent from other cytokine receptors, including γc. Thus, SOCS3 has been considered a selective suppressor of gp130 family cytokines, but not γc cytokines. Considering that γc signaling induces SOCS3 expression in T cells, here we revisited the role of SOCS3 on γc signaling. Using SOCS3 transgenic mice, we found that increased abundance of SOCS3 not only suppressed signaling of the gp130 family cytokine IL‐6, but also signaling of the γc family cytokine IL‐7. Consequently, SOCS3 transgenic mice were impaired in IL‐7‐dependent T cell development in the thymus and the homeostasis of mature T cells in peripheral tissues. Moreover, enforced SOCS3 expression interfered with the generation of Foxp3+ regulatory T cells that requires signaling by the γc family cytokine IL‐2. Collectively, we report an underappreciated role for SOCS3 in suppressing γc cytokine signaling, effectively expanding its scope of target cytokines in T cell immunity. [ABSTRACT FROM AUTHOR]

V-(D)-J recombination generates the antigen receptor diversity necessary for immune cell function, while allelic exclusion ensures that each cell expresses a single antigen receptor. V-(D)-J recombination of the Ig, Tcrb, Tcrg and Tcrd antigen receptor genes is ordered and sequential so that only one allele generates a productive rearrangement. The mechanism controlling sequential rearrangement of antigen receptor genes, in particular how only one allele is selected to initiate recombination while at least temporarily leaving the other intact, remains unresolved. Genomic imprinting, a widespread phenomenon wherein maternal or paternal allele inheritance determines allele activity, could represent a regulatory mechanism for controlling sequential V-(D)-J rearrangement. We used strain-specific single-nucleotide polymorphisms within antigen receptor genes to determine if maternal vs paternal inheritance could underlie chromosomal choice for the initiation of recombination. We found no parental chromosomal bias in the initiation of V-(D)-J recombination in T or B cells, eliminating genomic imprinting as a potential regulator for this tightly regulated process. [ABSTRACT FROM AUTHOR]

Thymocyte development requires the coordinated input of signals that originate from numerous cell surface molecules. Although the majority of thymocyte signal-initiating receptors are lineage-specific, most trigger 'ubiquitous' downstream signaling pathways. T-lineage-specific receptors are coupled to these signaling pathways by lymphocyte-restricted adapter molecules. We and others recently identified a new putative adapter protein, Themis1, whose expression is largely restricted to the T lineage. Mice lacking Themis1 exhibit a severe block in thymocyte development and a striking paucity of mature T cells revealing a critical role for Themis1 in T-cell maturation. Themis1 orthologs contain three conserved domains: a proline-rich region (PRR) that binds to the ubiquitous cytosolic adapter Grb2, a nuclear localization sequence (NLS), and two copies of a novel cysteine-containing globular (CABIT) domain. In the present study, we evaluated the functional importance of each of these motifs by retroviral reconstitution of Themis1−/− progenitor cells. The results demonstrate an essential requirement for the PRR and NLS motifs but not the conserved CABIT cysteines for Themis1 function. [ABSTRACT FROM AUTHOR]

CD4+ helper T cells are essential for immune responses and differentiate in the thymus from CD4+ CD8+ 'double-positive' ( DP) thymocytes. The transcription factor Runx3 inhibits CD4+ T-cell differentiation by repressing Cd4 gene expression; accordingly, Runx3 is not expressed in DP thymocytes or developing CD4+ T cells. The transcription factor Thpok is upregulated in CD4-differentiating thymocytes and required to repress Runx3. However, how Runx3 is controlled at early stages of CD4+ T-cell differentiation, before the onset of Thpok expression, remains unknown. Here we show that Gata3, a transcription factor preferentially and transiently upregulated by CD4+ T-cell precursors, represses Runx3 and binds the Runx3 locus in vivo. Accordingly, we show that high-level Gata3 expression and expression of Runx3 are mutually exclusive. Furthermore, whereas Runx3 represses Cd4, we show that Gata3 promotes Cd4 expression in Thpok-deficient thymocytes. Thus, in addition to its previously documented role in promoting CD4-lineage gene-expression, Gata3 represses CD8-lineage gene expression. These findings identify Gata3 as a critical pivot of CD4- CD8 lineage differentiation. [ABSTRACT FROM AUTHOR]

Immature thymocytes are bipotential cells that are signalled during positive selection to become either helper- or cytotoxic-lineage T cells. By tracking expression of lineage determining transcription factors during positive selection, we now report that the Cd8 coreceptor gene locus co-opts any coreceptor protein encoded within it to induce thymocytes to express the cytotoxic-lineage factor Runx3 and to adopt the cytotoxic-lineage fate, findings we refer to as 'coreceptor gene imprinting'. Specifically, encoding CD4 proteins in the endogenous Cd8 gene locus caused major histocompatibility complex class II-specific thymocytes to express Runx3 during positive selection and to differentiate into CD4+ cytotoxic-lineage T cells. Our findings further indicate that coreceptor gene imprinting derives from the dynamic regulation of specific cis Cd8 gene enhancer elements by positive selection signals in the thymus. Thus, for coreceptor-dependent thymocytes, lineage fate is determined by Cd4 and Cd8 coreceptor gene loci and not by the specificity of T-cell antigen receptor/coreceptor signalling. This study identifies coreceptor gene imprinting as a critical determinant of lineage fate determination in the thymus. [ABSTRACT FROM AUTHOR]

Since the discovery of γδ T cells two decades ago, considerable effort has been made to understand their developmental program, their antigen specificity, and their contribution to the immune response. In this review, we focus on what is known about γδ T-cell development and on the advances that have been made in determining which genes are required. In addition, we compare the genetic requirements for αβ and γδ T-cell development with the hope of gaining a better picture of the signaling pathways that govern the development of γδ lineage cells. [ABSTRACT FROM AUTHOR]

How equipotent cells develop into complex tissues containing many diverse cell types is still a mystery. However, evidence is accumulating from different tissue systems in multiple organisms that many of the specific receptor families known to regulate cell fate decisions target conserved signaling pathways. A mechanism for preserving specificity in the cellular response that has emerged from these studies is one in which quantitative differences in receptor signaling regulate the cell fate decision. A signal strength model has recently gained support as a means to explain αβ/γδ lineage commitment. In this review, we compare the αβ/γδ fate decision with other cell fate decisions that occur outside of the lymphoid system to attain a better picture of the quantitative signaling mechanism for cell fate specification. [ABSTRACT FROM AUTHOR]

The two iron regulatory proteins IRP1 and IRP2 bind to transcripts of ferritin, transferrin receptor and other target genes to control the expression of iron metabolism proteins at the post-transcriptional level. Here we compare the effects of genetic ablation of IRP1 to IRP2 in mice. IRP1-/- mice misregulate iron metabolism only in the kidney and brown fat, two tissues in which the endogenous expression level of IRP1 greatly exceeds that of IRP2, whereas IRP2-/- mice misregulate the expression of target proteins in all tissues. Surprisingly, the RNA-binding activity of IRP1 does not increase in animals on a lowiron diet that is sufficient to activate IRP2. In animal tissues, most of the bifunctional IRP1 is in the form of cytosolic aconitase rather than an RNA-binding protein. Our findings indicate that the small RNA-binding fraction of IRP1, which is insensitive to cellular iron status, contributes to basal mammalian iron homeostasis, whereas IRP2 is sensitive to iron status and can compensate for the loss of IRP1 by increasing its binding activity. Thus, IRP2 dominates post-transcriptional regulation of iron metabolism in mammals. [ABSTRACT FROM AUTHOR]

Adapter molecules in a variety of signal transduction systems link receptors to a limited number of commonly used downstream signaling pathways. During T-cell development and mature T-cell effector function, a multi-chain receptor (the pre-T-cell antigen receptor or the T-cell antigen receptor) activates several protein tyrosine kinases. Receptor and kinase activation is linked to distal signaling pathways (PLC-γ1 activation, Ca[sup 2+] influx, PKC activation and Ras/Erk activation) via the adapter protein LAT (Linker for Activation of T cells). Structure/function studies of LAT including expression of selected LAT point mutations in vivo reveals that these multiple pathways are integrated at the level of the LAT adapter. These studies suggest that similar levels of control may be found in other systems where adapter molecules are known to have important functions. [ABSTRACT FROM AUTHOR]

The T cell antigen receptor (TCR) is a multimeric complex composed of an antigen-binding clonotypic heterodimer and a signal transducing complex consisting of the CD3 dimers (CD3ϒε and CD3δε) and a TCR-ς homodimer. In all jawed vertebrates there are two T cell lineages, αβ and ϒδ, distinguished by the clonotypic subunits contained within their TCRs (TCR-α and -β or TCR-ϒ and -δ respectively). A third receptor complex, the preTCR, is only expressed on immature T cells. The preTCR, which contains the invariant pre-Tα (pTα) chain in lieu of TCR-α, plays a critical role in the early development of αβ lineage cells. The subunit composition of the signal transducing complexes of the pre-, α&beta:- and ϒδTCRs was previously thought to be identical. However, recent data demonstrate that there are significant differences in the signal transducing complexes of these three TCRs. For example, αβTCRs contain both CD3ϒε and CD3δε dimers, whereas ϒδTCRs contain only CD3ϒε dimers. Moreover, preTCR function appears to be unaffected in the absence of CD3δ, suggesting that CD3δ&epsilon dimers are dispensable for pre-TCR assembly. In this review, we summarize current data relating to the subunit composition of the pre-, αβ- and ϒδTCRs and discuss how these structural differences may impact receptor signaling and αβ/ϒδ lineage determination. [ABSTRACT FROM AUTHOR]