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RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) is a chemoattractant cytokine (chemokine) important in the generation of inflammatory infiltrate and human immunodeficiency virus entry into immune cells. RANTES is expressed late (3-5 days) after activation in T lymphocytes. Using expression cloning, we identified the first ''late'' T lymphocyte associated transcription factor...
ICAM-2-deficient mice exhibit prolonged accumulation of eosinophils in lung interstitium concomitant with a delayed increase in eosinophil numbers in the airway lumen during the development of allergic lung inflammation. The ICAM-2-dependent increased and prolonged accumulation of eosinophils in lung interstitium results in prolonged, heightened airway hyperresponsiveness. These findings reveal an...
The crystal structure of the extracellular domain of CD94, a component of the CD94/NKG2 NK cell receptor, has been determined to 2.6 Å resolution, revealing a unique variation of the C-type lectin fold. In this variation, the second α helix, corresponding to residues 102-112, is replaced by a loop, the putative carbohydrate-binding site is significantly altered, and the Ca 2+ -binding...
Although nitric oxide (NO) kills or inhibits the replication of a variety of intracellular pathogens, the antimicrobial mechanisms of NO are unknown. Here, we identify a viral protease as a target of NO. The life cycle of many viruses depends upon viral proteases that cleave viral polyproteins into individual polypeptides. NO inactivates the Coxsackievirus protease 3C, an enzyme necessary for the...
Two synthetic O-GIcNAc-bearing peptides that elicit H-2D b -restricted glycopeptide-specific cytotoxic T cells (CTL) have been shown to display nonreciprocal patterns of cross-reactivity. Here, we present the crystal structures of the H-2D b glycopeptide complexes to 2.85 Å resolution or better. In both cases, the glycan is solvent exposed and available for direct recognition by the...
Signaling through the B cell receptor (BCR) is essential for B cell function and development. Despite the key role of Syk in BCR signaling, little is known about the mechanism by which Syk transmits downstream effectors. BLNK (B cell LiNKer protein), a substrate for Syk, is now shown to be essential in activating phospholipase C (PLC)γ2 and JNK. The BCR-induced PLCγ2 activation, but not the JNK activation,...
We have generated mice with a cell type-specific disruption of the Stat3 gene in macrophages and neutrophils. The mutant mice are highly susceptible to endotoxin shock with increased production of inflammatory cytokines such as TNFα, IL-1, IFNγ, and IL-6. Endotoxin-induced production of inflammatory cytokines is augmented because the suppressive effects of IL-10 on inflammatory cytokine production...
An interleukin-18 binding protein (IL-18BP) was purified from urine by chromatography on IL-18 beads, sequenced, cloned, and expressed in COS7 cells. IL-18BP abolished IL-18 induction of interferon-γ IFNγ), IL-8, and activation of NF-κB in vitro. Administration of IL-18BP to mice abrogated circulating IFNγ following LPS. Thus, IL-18BP functions as an inhibitor of the early Th1 cytokine response. IL-18BP...
In H2-M - mice, the presence of a single peptide, CLIP, bound to MHC class II molecules generates a diverse repertoire of CD4 + cells. In these mice, typical self-peptides are not bound to class II molecules, with the result that a very high proportion of H2-M - CD4 + cells are responsive to the various peptides displayed on normal MHC-compatible APC. We show here,...
The two genetically established antimicrobial mechanisms of macrophages are production of reactive oxygen intermediates by phagocyte oxidase (phox) and reactive nitrogen intermediates by inducible nitric oxide synthase (NOS2). Mice doubly deficient in both enzymes (gp91 phox-/- //NOS2 -/- ) formed massive abscesses containing commensal organisms,...
T cell receptor (TCR) recognition of nonpeptidic and modified peptide antigens has been recently uncovered but is still poorly understood. Immunization with an H-2K b -restricted glycopeptide RGY8-6H-Gal 2 generates a population of cytotoxic T cells that express both α/β TCR, specific for glycopeptide, and γ/δ TCR, specific for the disaccharide, even on glycolipids. The crystal structure...
Interleukin 6 (IL-6) is the major survival factor for myeloma tumor cells and induces signaling through the STAT proteins. We report that one STAT family member, Stat3, is constitutively activated in bone marrow mononuclear cells from patients with multiple myeloma and in the IL-6-dependent human myeloma cell line U266. Moreover, U266 cells are inherently resistant to Fas-mediated apoptosis and express...
The proto-oncogene Cot/Tpl-2 encodes a MAP3K- related serine-threonine kinase. Expression of wild type Cot activates the IκB kinases (IKK) leading to induction of NF-κB. Conversely, expression of kinase-deficient Cot inhibits CD3/CD28 but not TNFα induction of NF-κB. These findings suggest the selective involvement of Cot/Tpl-2 or a closely related kinase in the CD3/CD28 costimulatory pathway leading...
While the majority of purified pluripotential hematopoietic stem cells (PHSC) express c-Kit, the receptor for steel factor, we have phenotypically and functionally separated a distinct class of PHSC that does not express c-Kit. In contrast to c-Kit-postive (c-Kit pos ) PHSC, the c-Kit-negative (c-Kit neg ) PHSC do not proliferate in response to multiple hematopoietic...
B cell antigen receptor (BCR) ligation leads to receptor desensitization wherein BCR remain competent to bind antigen and yet fail to transduce signals. Desensitized BCR exhibit a defect at the most proximal level of signal transduction, consistent with failed transmission of signals through the receptor complex. We report that antigen stimulation leads to dissociation or destabilization of the BCR...
In mammals, the Rho family GTPase Rac2 is restricted in expression to hematopoietic cells, where it is coexpressed with Rac1. Rac2-deficient mice were created to define the physiological requirement for two near-identical Rac proteins in hematopoietic cells. rac2 -/- neutrophils displayed significant defects in chemotaxis, in shear-dependent L-selectin-mediated capture on the endothelial...
The bare lymphocyte syndrome (BLS) is characterized by the absence of MHC class II transcription and humoral- and cellular-mediated immune responses to foreign antigens. Three of the four BLS genetic complementation groups have defects in the activity of the MHC class II transcription factor RFX. We have purified the RFX complex and sequenced its three subunits. The sequence of the smallest subunit...
Cathepsins have been implicated in the degradation of proteins destined for the MHC class II processing pathway and in the proteolytic removal of invariant chain (Ii), a critical regulator of MHC class II function. Mice lacking the lysosomal cysteine proteinase cathepsin S (catS) demonstrated a profound inhibition of Ii degradation in professional APC in vivo. A marked variation in the generation...
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