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Novel CNS Autoimmunity Model
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70% in DOX-treated mice injected with liposomes containing a compound that induced apoptosis of circulating monocytes and DCs. Suspension of DOX treatment after 10 days resulted in a chronic demyelinating neuroinflammatory disease with CD8+ T cell infiltration. This novel model of acute CNS disease involves CCL2-induced infiltration of monocytes and DCs into the CNS of transgenic mice conditionally expressing FLT3L; chronic demyelinating disease with T cell involvement occurs after cessation of FLT3L expression. Regulating CD1A Transcription
Although expression of CD1a, a molecule that presents lipid Ag to a restricted set of T cells, is limited to a few cell types, factors regulating its expression are unknown. CD1A mRNA transcription was found by Colmone et al. (p. 7024 ) to correlate directly with protein expression levels on human T cells. Analyses of reporter constructs defined a 1000-bp fragment as sufficient and required for CD1A promoter activity. Single base pair mutations in four transcription factor binding sites identified by computer search programs resulted in decreased promoter activity. Proteins binding CD1A were detected by EMSA on nuclear extracts of human T leukemia cells and identified as CREB-1 and activating transcription factor-2 (ATF-2) using specific Abs in supershift experiments and chromatin immunoprecipitation assays. CD1A promoter activity and mRNA levels decreased in cells treated with a cAMP activator that phosphorylated and activated ATF/CREB family members; increased promoter activity occurred in cells cotransfected with a vector expressing a dominant-negative CREB plus the CD1A reporter construct. Vector-expressed short hairpin RNA specific for ATF-2 decreased ATF-2 mRNA expression in T cell lines, whereas short hairpin RNA specific for CREB-1 resulted in decreased expression of CREB-1, ATF-2, and CD1A mRNA. Chromatin immunoprecipitation assays using anti-CREB-1 or anti-ATF-2 Abs with primary human PBMC extracts showed more binding of ATF-2 in CD1a– monocytes compared with CD1a+ monocyte-derived dendritic cells. Thus, ATF-2 and CREB-1 regulate CD1A transcription by direct binding to its promoter in human cells in vivo and in vitro.
Limiting TB in T Cell-Deficient Hosts
Although production of IFN-
by T cells controls Mycobacterium tuberculosis infection, any contribution of IFN- produced by NK cells is unknown. Feng et al. (p. 7086
) detected high levels of intracellular IFN- in naive NK cells from RAG–/– mice stimulated in vitro with live M. tuberculosis and in NK cells from lungs of mice infected 4 wk earlier. Whereas RAG–/– mice were able to survive infection longer than 40 days postinfection, IFN-–/– mice or RAG–/– mice lacking NK cells or IL-12p40, or treated with anti-IFN- mAb, died by 30 days. Survival rates correlated inversely with number of bacteria, number and size of lesions, and number of infiltrating granulocytes in their lungs. Exogenous IL-12 restored the IFN- response to bacteria-stimulated splenocytes from RAG–/– animals lacking IL-12p40 or IL-12p35 but not to those lacking NK cells. Lung pathology was more severe in RAG–/– animals lacking IL-12p40 vs IL-12p35. Only infected RAG–/– mice up-regulated NO synthetase type 2 expression in pulmonary macrophages, whereas modulators of its expression were down-regulated compared with the other mutant strains or with anti-IFN- mAb-treated RAG–/– controls. Neutrophil chemotactic chemokine production was elevated in infected RAG–/– mice lacking IL-12p40 or treated with anti-IFN- mAb, whereas bacterial titers and lung pathology were increased in infected anti-IFN- mAb-treated RAG–/– mice depleted of neutrophils. The authors propose that IFN- produced by NK cells cooperates with IL-12 to protect mice lacking T cells against M. tuberculosis infection via activation of macrophage microbicidal activity and neutrophil infiltration.
TCR Specificity and Degeneracy
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Factoring B Cell Maturation
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Two Pathways to DNA Vaccination
Developing potent CD8+ T cell memory responses, a challenge in DNA vaccination strategies, is dependent on CD4+ T cell help at priming. To optimize vaccine design, Radcliffe et al. (p. 6626
) compared the Ag presentation pathways of two fusion DNA vaccines. They injected naive mice with pDUO (a DNA plasmid carrying an endoplasmic reticulum-targeted OVA peptide fused to a core peptide sequence from the N-terminal domain of tetanus toxin fragment C inserted into the mouse invariant chain to replace the CLIP sequence). The animals had several-fold higher numbers of IFN--producing T cells compared with mice vaccinated with the OVA peptide fused to the toxin fragment alone (pDOM-SL8). CD4+ T cell depletion reduced the pDUO and pDOM-SL8 responses; CD8+ T cell expansion was greater and lasted longer with pDUO vaccination. Transfer experiments with naive CFSE-labeled OVA peptide-specific TCR transgenic cells showed that OVA peptide from injected donor cells transfected with pDUO was presented directly by cells that matched the MHC of the mice; OVA peptide from pDOM-SL8 transgenic cells was cross-presented by MHC mismatched cells as well, even in the absence of TAP2. Mice primed with pDUO and challenged 50 days later with pDOM-SL8, or vice versa, had higher memory and cytolytic CD8+ T cell responses than mice boosted with the priming vaccine. The authors demonstrate that alternating direct and cross-presentation of Ags delivered by DNA vaccines results in heightened effector and memory CD8+ T cell responses.
Human Monocyte/Macrophage Transcriptome
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treatment of M-CSF-differentiated macrophages was accompanied by significant early modification of the monocyte maturation global transcriptome; macrophages polarized to M2 by IL-4 treatment had only subtle adjustments to the transcriptome. Gene ontology analyses of gene clusters identified in monocyte-to-macrophage differentiation showed changes in proteins involved in cell cycle, lipid metabolism, and immune response. M1 polarization was accompanied by massive changes in transcripts associated with classical macrophage activation, including DNA transcription, protein metabolism, and proinflammatory cytokines; M2 polarization was accompanied by less dramatic changes in cytokines, chemokines, and scavenger receptors. G protein-coupled receptor repertoires varied with the stage of monocyte differentiation and macrophage polarization. This global profiling approach identifies stage-specific genes modulated during human macrophage differentiation and polarization and points to differences with the mouse profile. Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
Differentially Regulates Innate Resistance and Neutrophil Response in T Cell-Deficient Hosts Infected with Mycobacterium tuberculosis
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