The phagosome: compartment with a license to kill

Phagosomes are fascinating subcellular structures. After all, there are only a few compartments that are born before our very eyes and whose development we can follow in a light microscope until their contents disintegrate and are completely absorbed. Yet, some phagosomes are taken advantage of by pathogenic microorganisms, which change their fate. Research into phagosome biogenesis has flourished in recent years - the purpose of this review is to give a glimpse of where this research stands, with emphasis on the cell biology of macrophage phagosomes, on new model organisms for the study of phagosome biogenesis and on intracellular pathogens and their interference with normal phagosome function.     

Neutrophils with a license to kill: permeabilized,not stirred

The neutrophil responds to invading microorganisms in part by assembling the NADPH oxidase complex and producing superoxide radicals. Relatively little is known about the intracellular assembly or activation of the oxidase, but Brown et al. in the January issue of Molecular Cell provide a useful strategy involving permeabilized neutrophils to tackle this question.     

Lens cells: more than meets the eye

Lens cells originate from the head ectoderm and differentiate into an avascular organ constituted from two contiguous cell subpopulations of very different morphology. Lens cells, together with corneal cells, are responsible for the transmission and focusing of light onto the retina. Loss of transparency within the lens, via disruption of membrane transport or protein aggregation, results in cataract.     

Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells

Iron (Fe) and aluminum (Al) have been implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we examined neuronal and glial cells to clarify which contributes most to metal accumulation after internalization through the transferrin-independent iron uptake (Tf-IU) systems in primary neuronal and glial predominant (NP and GP) cells from rat cerebral cortex, which affect the accumulation of transition metals in a variety of cultured cells. Al more significantly upregulated the Tf-IU activity in GP cells than in NP cells. GP cells were more resistant to Fe and Al exposure than NP cells. However, a chemiluminescence analysis specific for reactive oxygen species (ROS) showed that ROS levels in Fe- or Al-loaded NP cells were twice as high as in Fe- or Al-loaded GP cells. Northern blot analysis and gel retardation assay showed that the Al and Fe exposure taken up by the cells suppress Tf receptor mRNA expression to a greater extent in GP than NP cells, indicating that Al and Fe more markedly accumulate in glial than in neuronal cells. These results suggest that glial cells rather than neuronal cells contribute to the metal accumulation and are more resistant to oxidative stress caused by metals than neuronal cells. The present study may help to explain the pathogenesis of neurodegeneration in AD disorders caused by metal-generated oxidative stress.     

Regulatory T cells and tumor immunity

Central deletion of self-reactive T cells has been the textbook paradigm for inducing self-tolerance in the periphery and the concept of a role of T cell-mediated suppression in this process has long been controversial. A decisive shift in the opinion on suppressor T cells has lately occurred with the observations of Sakaguchis group that linked a class of CD4+CD25+ T cells to the prevention of autoimmunity from neonatal thymectomy in mice. These CD4+CD25+ T cells have been named T regulatory (Treg) cells. They are believed to be selected in the thymus as an anti-self repertoire. Hence they were referred to as natural T regulatory (nTreg) cells. Presently, in addition to their role in autoimmunity, they are believed to exert regulatory function in infection, in transplantation immunity as well as in tumor immunity. In contrast to these nTreg cells, another class of CD4+ Treg cells also exercises regulatory function in the periphery. These Treg cells are also CD4+ T cells and after activation they also become phenotypically CD4+CD25+. They are, however induced in the periphery as Treg cells. Hence, they are termed as induced Treg (iTreg) cells. There are major differences in the biology of these two types of Treg cells. They differ in their requirements for activation and in their mode of action. Nonetheless, evidence indicates that both nTreg cells and iTreg cells are involved in the control of tumor immunity. The question of how to circumvent their regulatory constraints, therefore, has become a major challenge for tumor immunologists.     

IgG antibodies to asialoGM1 are more sensitive than IgM antibodies to kill in vivo natural killer cells and prematured cytotoxic T lymphocytes of mouse spleen

IgG and IgM antibodies, which were isolated from the anti-asialoGM1 (GA1) serum, had different effects against natural killer (NK) and prematured cytotoxic T cells (CTLs) in in vivo administration and in in vitro treatment. In in vitro treatments, the IgM antibody killed NK cells of nude mouse spleen in the presence of complement (C') 12 times more potently than the IgG antibody did, and either antibody with C' killed pre-CTL. In in vivo administrations, only the IgG antibody was effective in diminishing NK activity of the nude mouse spleen cells and in suppressing antigen-specific CTL induction from primed spleen cells by in vitro stimulation with X-irradiated tumor cells. The IgM antibody was not effective at all in either system. The in vivo effect of the IgG on NK activity was blocked by preadministration with silica or carrageenan but not by that with cobra venom factor (CVF). These results indicate that in vivo administration of anti-GA1 antiserum leads to macrophage-mediated depletion of CTL precursors as well as NK cells.     

Lamprey serum can kill HeLa and NB4 tumor cells

Nature consists primarily of living materials, many of which are pathogenic microorganisms capable of killing and converting other organisms into copies of themselves . For self-defense, eukaryotes have gradually evolved immune systems, including the innate and adaptive immune systems . Innate immunity has been found in plants, fungi, and metazoans; while jawed vertebrates have an evolved adaptive immune system in addition to the innate immunity defense . Agnathans, represented by lamprey and hagfish, are the oldest vertebrates that possess the adaptive immune defenses, although whether TCR and BCR exist in jawless vertebrates remains unknown.     

Adherent cells in tumor immunity

The present studies explored the role of adherent cells in tumor immunity. Lymph node cells from mice bearing large tumors appeared to be maximally stimulated in vivo and incapable of further stimulation by cells of the same tumor in vitro. Removal of the adherent cell population resulted in a marked decrease in the spontaneous background activity of the remaining nonadherent cells and allowed these cells to undergo stimulation when cultured in the presence of mitomycin-blocked tumor cells. The role of the adherent cell in the maintenance of a state of continuous stimulation was further elucidated by experiments in which lymph node cell populations were reconstituted from the adherent and nonadherent subpopulations. It was also shown that adherent lymphoid cells from tumor-bearing mice, but not from normal mice, were capable of stimulating tumor-immune lymphocytes in a manner similar to intact mitomycin-blocked tumor cells.     

Lipolysis: more than just a lipase

Successful adaptation to starvation in mammals depends heavily on the regulated mobilization of fatty acids from triacylglycerols stored in adipose tissue. Although it has long been recognized that cyclic AMP represents the critical second messenger and hormone-sensitive lipase (HSL)**Abbreviations used in this paper: ADRP, adipocyte differentiation-related protein; HSL, hormone-sensitive lipase; PKA, protein kinase A; TAG, triacylglycerol. the rate-determining enzyme for lipolysis, simple activation of the enzyme has failed to account for the robust augmentation of fatty release in response to physiological agonists. In this issue, Sztalryd et al. (2003) provide convincing support to the notion that the subcellular compartmentalization of lipase also regulates lipolysis, and, more importantly, that proteins other than HSL are localized to the lipid droplet and are indispensable for its optimal hydrolysis.     

Mitochondria: more than just a powerhouse

Pioneering biochemical studies have long forged the concept that the mitochondria are the 'energy powerhouse of the cell'. These studies, combined with the unique evolutionary origin of the mitochondria, led the way to decades of research focusing on the organelle as an essential, yet independent, functional component of the cell. Recently, however, our conceptual view of this isolated organelle has been profoundly altered with the discovery that mitochondria function within an integrated reticulum that is continually remodeled by both fusion and fission events. The identification of a number of proteins that regulate these activities is beginning to provide mechanistic details of mitochondrial membrane remodeling. However, the broader question remains regarding the underlying purpose of mitochondrial dynamics and the translation of these morphological transitions into altered functional output. One hypothesis has been that mitochondrial respiration and metabolism may be spatially and temporally regulated by the architecture and positioning of the organelle. Recent evidence supports and expands this idea by demonstrating that mitochondria are an integral part of multiple cell signaling cascades. Interestingly, proteins such as GTPases, kinases and phosphatases are involved in bi-directional communication between the mitochondrial reticulum and the rest of the cell. These proteins link mitochondrial function and dynamics to the regulation of metabolism, cell-cycle control, development, antiviral responses and cell death. In this review we will highlight the emerging evidence that provides molecular definition to mitochondria as a central platform in the execution of diverse cellular events.