Evidence for increased T cell turnover and decreased thymic output in HIV infection.

The effects of HIV infection upon the thymus and peripheral T cell turnover have been implicated in the pathogenesis of AIDS. In this study, we investigated whether decreased thymic output, increased T cell proliferation, or both can occur in HIV infection. We measured peripheral blood levels of TCR rearrangement excision circles (TREC) and parameters of cell proliferation, including Ki67 expression and ex vivo bromodeoxyuridine incorporation in 22 individuals with early untreated HIV disease and in 15 HIV-infected individuals undergoing temporary interruption of therapy. We found an inverse association between increased T cell proliferation with rapid viral recrudescence and a decrease in TREC levels. However, during early HIV infection, we found that CD45RO-CD27high (naive) CD4+ T cell proliferation did not increase, despite a loss of TREC within naive CD4+ T cells. A possible explanation for this is that decreased thymic output occurs in HIV-infected humans. This suggests that the loss of TREC during HIV infection can arise from a combination of increased T cell proliferation and decreased thymic output, and that both mechanisms can contribute to the perturbations in T cell homeostasis that underlie the pathogenesis of AIDS.     

HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism.

HIV-1 induces apoptosis and leads to CD4+ T-lymphocyte depletion in humans. It is still unclear whether HIV-1 kills infected cells directly or indirectly. To elucidate the mechanisms of HIV-1-induced apoptosis, we infected human CD4+ T cells with HIV-1. Enzymatic analysis with fluorometric substrates showed that caspase 2, 3, and 9 were activated in CD4+ T cells with peak levels 48 h after infection. Immunoblotting analysis confirmed the cleavage of pro-caspase 3 and 9, and of specific caspase substrates. Release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria was observed in HIV-infected cells. The cytochrome c and AIF release preceded the reduction of the mitochondrial transmembrane potential and nuclear chromatin condensation. H IV infection led to phosphorylation of p53 at the Ser15 residue, detectable as early as 24 h after infection. The p53 phosphorylation was followed by increased mRNA and protein expression of p21, Bax, HDM2, and p53. Up-regulation of surface FasL expression, accompanied by a down-regulation of Fas-associated proteins (FADD, DAXX, and RIP), was observed 72 h after infection. Our results suggest that HIV activates the p53 pathway, leading to cytochrome c and AIF release with ensuing caspase activation.     

Antigen presentation by macrophage-enriched cells from the mouse Peyer's patch

Macrophage-enriched cells derived from Peyer's patches were prepared with or without preincubation of whole patches in collagenase-containing medium. The cells thus obtained were pulsed with ovalbumin (OVA), added to OVA-primed whole lymph node (LN) cells or LN T cells and proliferative responses stimulated in the latter cells were assessed after 5 days by thymidine incorporation. Macrophage-enriched cells obtained from Peyer's patches (PP) preincubated with collagenase presented antigen as well or better than macrophage-enriched cells obtained from spleens. In contrast, macrophage-enriched cells obtained from PP which were not preincubated with collagenase were frequently unable to function as antigen-presenting cells. In further studies, macrophage-enriched cells obtained from mice which had been fed OVA were found to be capable of stimulating antigen-primed LN T cells in an antigen-specific manner without further exposure to antigen in vitro. These results indicate PP macrophage-enriched cells are fully capable of supporting the induction of immune responses in vitro and that macrophages from PP of orally primed mice may present antigen without further antigen exposure. Thus macrophages in PP may participate in the induction of immune responses to gastrointestinal antigens in vivo.     

Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

1. Download : Download high-res image (226KB)
2. Download : Download full-size image

     

The synchronization of voices by gelada monkeys

Evidence is presented from recordings made from captive gelada monkeys (Theropithecus gelada) that these monkeys are capable of synchronizing the onsets of their own vocal sounds to the anticipated onsets of sounds produced by other gelada voices. The possibility is discussed that in order to synchronize the onsets of their own sounds to the anticipated onsets of sounds made by other voices, such gelada voices have to possess the ability to “figure out” the tempo and rhythm of the vocal strings produced by the other voices and precisely control the timing of their own voices. It is suggested that geladas do synchronize their voices by using precise temporal and rhythmical controls on the outputs of their voices that are analogous to the temporal and rhythmical abilities humans use in many of the supra-segmental aspects of speech.     

Epithelial-mesenchymal interactions in the outgrowth of limb buds and facial primordia in chick embryos.

The facial primordia in the chick embryo begin as rounded swellings that surround the primitive mouth and these grow out to form the beak. The control of proximodistal outgrowth is not well understood but may involve similar mechanisms to the limb bud. In order to test this hypothesis, combinations were made between epithelium and mesenchyme from facial primordia and limb buds. Signals from all three types of facial mesenchyme (frontonasal mass, mandibular, and maxillary) maintained the thickened apical ectodermal ridge of limb epithelium for up to 48 h. Combinations of tissues from the frontonasal mass mesenchyme and limb epithelium underwent substantial and correct morphogenesis. In contrast, poor development was observed in combinations with mandibular mesenchyme. Signals from frontonasal mass epithelium promoted outgrowth and morphogenesis of limb mesenchyme whereas mandibular and maxillary epithelium did not support joint morphogenesis. The results suggest that signals employed in the epithelial-mesenchymal interactions in facial primordia are similar but not identical to those signals used in the limb bud.     

Differential translational regulation of IRE-containing mRNAs in Drosophila melanogaster by endogenous IRP and a constitutive human IRP1 mutant

Insects, like vertebrates, express iron regulatory proteins (IRPs) that may regulate proteins in cellular iron storage and energy metabolism. Two mRNAs, an unspliced form of ferritin H mRNA and succinate dehydrogenase subunit b (SDHb) mRNA, are known to comprise an iron responsive element (IRE) in their 5'-untranslated region making them susceptible to translational repression by IRPs at low iron levels. We have investigated the effect of wild-type human IRP1 (hIRP1) and the constitutively active mutant hIRP1-S437 in transgenic Drosophila melanogaster. Endogenous Drosophila IRE-binding activity was readily detected in gel retardation assays. However, translational repression assessed by polysome gradients was only visible for unspliced IRE-containing ferritin H mRNA, but not for SDHb mRNA. Upon expression of exogenous hIRP1-S437 both mRNAs were strongly repressed. This correlated with a diminished survival rate of adult flies with hIRP1 and complete lethality with hIRP1-S437. We conclude that constitutive IRP1 expression is deleterious to fly survival, probably due to the essential function of SDHb or proteins encoded by yet unidentified target mRNAs.