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Lyn regulation of asthma
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, than controls. Lyn–/– dendritic cells (DC) had a more immature phenotype, and Ag-pulsed Lyn–/– DC exhibited less phosphorylation of paired Ig-like receptor B; LPS stimulation induced less IL-12 production and less phosphorylation of SH2-domain-containing inositol 5-phosphatase-1 compared with controls. Naive Lyn+/+ mice adoptively transferred with OVA-pulsed Lyn–/– DC had greater mucosal inflammation and exaggerated cytokine production than recipients of OVA-pulsed Lyn+/+ DC. The authors propose that DC are central to the critical role played by Lyn in this mouse model of asthma and suggest that Lyn negatively regulates Th2 mucosal inflammatory responses to Ag delivered by aerosol. A Th1-specific cell surface marker
Many cytokines and transcription factors influencing CD4+ T cell differentiation are known, but no Th1-specific cell surface molecules of defined function have been reported. Dardalhon et al. (p. 1558
) found that one of 20,000 mAbs produced in rats against established mouse Th1 cells bound Th1, but not Th2 or Th0, cells. The Th1-specific molecule was identified as CD226 by expression cloning and DNA sequencing. Flow cytometry showed that CD226 was expressed on nearly all naive CD8+ T cells and on 
40% of unactivated CD4+ T cells. Its expression was up-regulated on activated CD4+ T cells. Under in vitro polarizing conditions, CD226 was expressed at high levels on Th1 cells but was down-regulated on Th2 cells. SJL/J mice immunized with a myelin peptide and treated with either PBS or rat IgG developed Th1 spleen cells that proliferated in vitro in response to peptide and stained with peptide tetramers. The proliferative response was reduced in spleen cells from immunized mice treated with anti-CD226 mAb. Spleen and lymph node cells from the mAb-treated mice had reduced IFN-, and increased IL-2, IL-4, and IL-10, secretion; maximal inhibition of CD4+ T cell proliferation occurred using both T cells and CD11b+ cells from mAb-treated animals vs controls. Anti-CD226 mAb treatment delayed disease onset and reduced severity of experimental autoimmune encephalomyelitis induced in RAG-2–/– SJL/J mice by transfer of activated myelin peptide-specific Th1 cells compared with controls. The data demonstrate that CD226 is up-regulated on activated Th1 mouse cells and plays a costimulatory role in the effector phase of a Th1-driven disease model.
Diabetes resistance and CD8+ T cell tolerance
Although type 1 diabetes incidence is almost eliminated in NOD mice whose insulin-dependent diabetes (Idd) loci have been replaced by resistant alleles from nondiabetic strains of mice, the impact of those loci on islet Ag-specific CD8+ T cells is unknown. Martinez et al. (p. 1677 ) adoptively transferred purified CD8+ T cells from several strains of mice transgenic for a TCR specific for influenza virus hemagglutinin (HA) into syngeneic hosts expressing an HA transgene in their pancreatic islets (InsHA). Only transferred cells on a NOD background proliferated and increased in peripheral and pancreatic lymph nodes of NOD recipients; proliferation did not occur in InsHA-negative NOD mice. Both Idd3/5-InsHA and Idd9-InsHA mice were resistant to HA peptide-induced diabetes and had poor HA-specific CD8+ T cell responses. The Idd3/5-InsHA mice had less accumulation of the transferred CD8+ T cells, or adoptively transferred CD4+ T cells specific for islet Ags, in pancreatic lymph nodes compared with NOD-InsHA or Idd9-InsHA mice. Restoration of HA-TCR transgenic cell proliferation was accomplished by anti-CD25 mAb treatment of Idd3/5-InsHA recipients before transfer of congenic CD4+ T cells specific for islet Ags. Depletion of CD25+ T cells from purified recipient CD4+ T cells before co-injection with CD4+ T cells specific for HA also restored proliferation. The data indicate that resistance to type 1 diabetes is mediated by pancreatic lymph node CD4+CD25+ T cells in Idd3/5 transgenic mice but by a different mechanism in Idd9 transgenic mice.
Tumor Ag subversion of DC
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Lipid Ags and CD1 protein expression
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IKK/I
B signaling within neutrophil nuclei
Activation of neutrophils induces transcription of mediators, most with promoters containing B or B-like motifs. Resting neutrophils constitutively express NF-B proteins and their IB-
inhibitor in their nuclei. Ear et al. (p. 1834
) detected the , 
, and subunits of the IB kinase (IKK) signalosome in cytoplasm and nuclei of resting human neutrophils but only in PBMC cytoplasm. Both nuclear and cytoplasmic levels of IKK diminished within 10 min of LPS or TNF- stimulation of neutrophils but were restored within 2–3 h. IKK loss was partially inhibited by a proteasome inhibitor; its reappearance was prevented by cycloheximide. LPS and TNF- stimulation induced phosphorylation of IKK, IKK, IB-, and the NF-B subunit RelA in both nucleus and cytoplasm. Only IB- and RelA accumulated in the nucleus in cells treated with an inhibitor of nuclear export before stimulation. Cyclopentenone prostaglandins were the only kinase inhibitors tested that prevented LPS or TNF- stimulation-induced IKK phosphorylation, IB- degradation, and IKK loss, and reduced IKK and RelA phosphorylation. Detection of IKK, IKK, and IKK on immunoblots of sonicated nuclei from activated neutrophils suggested IKK association with chromatin. The data demonstrate that the main events of NF-B pathway activation occur in the nucleus as well as the cytoplasm of human neutrophils and are accompanied by transient loss of IKK in both locations.
Inducing osteoclast formation
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, or TNF- in cocultures of mouse hemopoietic osteoclast progenitors and primary osteoblasts, but MDP alone had no effect. MDP enhanced LPS-induced increases in receptor activator of NF-B ligand (RANKL) mRNA and ERK1/2 phosphorylation and a TNF--induced increase in RANKL expression in osteoblasts. Osteoclast formation was induced by IL-1, but not by LPS, in cocultures of wild-type osteoblasts and hemopoietic cells from wild-type mice and by TNF- in cocultures of wild-type osteoblasts and hemopoietic cells from mice deficient in Toll/IL-1R domain-containing adapter proteins. MDP enhanced both activities as well as TNF--induced RANKL mRNA expression in the latter cocultures. LPS stimulated expression of Nod2, an intracellular sensor of MDP, in osteoblasts from wild-type mice but not in those from mice deficient for either TLR4 or MyD88; Nod2 mRNA was induced in MyD88-deficient osteoblasts by TNF-. Small interference RNAs for Nod1 or Nod2 inhibited MDP-induced up-regulation of RANKL mRNA in osteoblasts. The authors propose that enhanced osteoclast formation induced by LPS or inflammatory cytokines occurs through MDP-induced, Nod2-mediated up-regulation of RANKL expression in osteoblasts. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
B Kinase Complex and Its Activation in Human Neutrophils
, and TNF- through Nucleotide-Binding Oligomerization Domain 2-Mediated Signaling in Osteoblasts
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