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A powerful weapon is critical to a soldier when battling with a strong enemy. In this issue of Immunity, Varinou et al. suggest that serine phosphorylation of Stat1, an important signal transducer and activator of transcription in interferon (IFN) signaling, is required for Stat1 to fight against a highly pathogenic infection.
Autoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of...
The homodimeric immunoreceptor NKG2D drives the activation of effector cells following engagement of diverse, conditionally expressed MHC class I-like protein ligands. NKG2D recognition is highly degenerate in that a single surface on receptor monomers binds pairs of distinct surfaces on each structurally divergent ligand, simultaneously accommodating multiple nonconservative ligand allelic or isoform...
The proliferative response of autoreactive rheumatoid factor (RF) B cells to mammalian chromatin-containing immune complexes (ICs) results from the sequential engagement of the B cell receptor (BCR) and Toll-like receptor 9 (TLR9). We have used ICs constructed from anti-hapten antibodies and defined haptenated dsDNA fragments to determine the form of mammalian DNA that mediates this process. Despite...
The transcription factor GATA-3 is expressed at every stage of thymic development, but its role in thymocyte differentiation is unknown. The fact that RAG chimeric animals lacking GATA-3 cannot generate early thymocytes from common lymphoid progenitors has thus far precluded investigation of the function of GATA-3 in the thymus. To address this, we generated mice deficient in GATA-3 at early and late...
Notch proteins are used repeatedly to direct developmental cell fate decisions in multiple organs. During hematopoiesis and immune development, Notch is critical for T/B lineage specification and for generation of splenic marginal zone B cells. In early embryonic development, Notch is crucial for generating hematopoietic stem cells. Emerging data suggest that Notch may also modulate the differentiation...
The signals that control decisions of progenitor commitment involve the interplay of both cytokines and transcription factors. Flt3L has emerged as a potential regulator of dendritic cell (DC) development, but regulation of HSC commitment to the DC lineage remains poorly understood. Our central finding is the identification of STAT3 activation as a checkpoint of Flt3L-regulated DC development. Deletion...
Recognition of MHC and MHC-like molecules by both natural killer (NK) and T cell receptors (TCR) reveals remarkable degeneracy. The interaction of the NKG2D NK receptor with several MHC I-like ligands has now been analyzed thermodynamically by McFarland and Strong, who suggest that a ''rigid adaptation'' mechanism governs such crossreactivity. This contrasts with ''induced fit'' that accounts for...
Expression of genes in the right place at the right time is fundamental to all of life. The ontogeny of effector and memory T cells is a robust example of this important principle. Although lymphocytes represent a late addition in animal evolution, they are serving as an exceptional model system to unlock the mysteries surrounding the way in which the genome is animated. It will be speculated here...
Factors involved in pregnancy failure due to abnormal fetomaternal tolerance are poorly understood. Here we describe distinct defects in placenta formation and subsequent pregnancy loss solely dependent on the activation of the complement alternative pathway and the effector mechanisms provided by the maternal C3. Surprisingly, this effect is independent of other complement activation pathways and...
Microbial infections induce chemokine and cytokine cascades that coordinate innate immune defenses. Infection with the intracellular bacterial pathogen Listeria monocytogenes induces CCR2-dependent monocyte recruitment and activation, an essential response for host survival. Herein we show that invasive L. monocytogenes, but not killed or noninvasive bacteria, induce secretion of MCP-1, the requisite...
We report that disruption of CD154 in nonobese diabetic (NOD) mice abrogates the helper function of CD4 + CD25 - T cells without impairing the regulatory activity of CD4 + CD25 + T cells. Whereas CD4 + T cells from NOD mice enhanced a diabetogenic CD8 + T cell response in monoclonal TCR-transgenic NOD mice, CD4 + T cells from NOD.CD154 -...
Stat1 is phosphorylated on serine 727 within its transactivating domain (TAD) in response to interferons or other immunological signals. We generated gene-targeted mutant mice expressing a serine727-alanine mutant of Stat1. These animals showed increased mortality upon infection with Listeria monocytogenes and impaired clearance of the bacteria from spleen and liver. The Stat1S727A mice were more...
CD40 -/- mice succumbed to low-dose aerosol infection with M. tuberculosis due to deficient IL-12 production leading to impaired priming of IFN-γ T cell responses. In contrast, CD40L -/- mice were resistant to M. tuberculosis. This asymmetry in outcome of infection between the two knockout strains is likely due to the existence of an alternative ligand for CD40...
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