Designing lymphocyte functional structure for optimal signal detection: voilà, T cells

One basic task of immune systems is to detect signals from unknown "intruders" amidst a noisy background of harmless signals. To clarify the functional importance of many observed lymphocyte properties, I ask: What properties would a cell have if one designed it according to the theory of optimal detection, with minimal regard for biological constraints? Sparse and reasonable assumptions about the statistics of available signals prove sufficient for deriving many features of the optimal functional structure, in an incremental and modular design. The use of one common formalism guarantees that all parts of the design collaborate to solve the detection task. Detection performance is computed at several stages of the design. Comparison between design variants reveals e.g. the importance of controlling the signal integration time. This predicts that an appropriate control mechanism should exist. Comparing the design to reality, I find a striking similarity with many features of T cells. For example, the formalism dictates clonal specificity, serial receptor triggering, (grades of) anergy, negative and positive selection, co-stimulation, high-zone tolerance, and clonal production of cytokines. Serious mismatches should be found if T cells were hindered by mechanistic constraints or vestiges of their (co-)evolutionary history, but I have not found clear examples. By contrast, fundamental mismatches abound when comparing the design to immune systems of e.g. invertebrates. The wide-ranging differences seem to hinge on the (in)ability to generate a large diversity of receptors.     

Habitat-dependent call divergence in the common cuckoo: is it a potential signal for assortative mating?

The common cuckoo (Cuculus canorus) is an obligate brood parasite that mimics the eggs of its hosts. The host-specific egg pattern is thought to be inherited matrilinearly, creating female-only host-specific races. Males are thought not to be adapted to their host and they maintain the species by mating arbitrarily with respect to host specialization of females. However, recent results suggest that male cuckoos may also show host-specific adaptations and these may require assortative mating with respect to host. The calls males produce on the breeding grounds could provide a potential mechanism for assortative mating. We tested whether male cuckoo calls differ more between nearby populations that parasitize different hosts than between distant populations that parasitize the same host. We recorded the calls of geographically distant pairs of populations in Hungary, with each pair consisting of a forest population and a nearby reed bed population. Each habitat is characterized by one main host species for the common cuckoo. Our results show that calls of distant cuckoo populations from the same habitat type are more similar to each other than they are to those of nearby populations from a different habitat. These results suggest that cuckoo calls differ sufficiently to allow recognition of habitat-specific individuals.     

Site-specific recombination in mammalian cells expressing the Int recombinase of bacteriophage HK022 – Site-specific recombination in mammalian cells promoted by a phage integrase

The int gene of bacteriophage HK022, coding for the integrase protein, was cloned in a mammalian expression vector downstream of the human cytomegalovirus (CMV) promoter. Green monkey kidney cells (COS-1) and mouse embryo fibroblast cells (NIH3T3) transiently transfected with the recombinant plasmid express the integrase protein. Co-transfection of this plasmid with reporter plasmids for site-specific recombination and PCR analyses show that the integrase promotes site-specific integration as well as excision. These reactions occurred without the need to supply integration host factor and excisionase, the accessory proteins that are required for integrase-promoted site-specific recombination in vitro as well as in the natural host Escherichia coli.     

Target cells for HIV in the central nervous system: macrophages or glial cells?

Infection of foetal or embryonic brain cells and cell lines from human astrocytomas and gliomas with HIV1 derived from T-lymphoma cultures leads to the expression of HIV in about 1 to 2% of the cells in culture. Single-cell cloning of astrocytoma cells shortly after infection resulted in the establishment of persistently HIV1-infected cell lines. These cultures were characterized by low production of virus and moderate intra- and extracellular expression of structural proteins. However, high expression of the nef regulatory protein was found. The virus could be rescued by cocultivation with T cells and primary macrophages giving rise to typical syncytia formation.In contrast to infection with HIV-infected T-lymphoma lines, cocultivation with HIV1-infected primary macrophages or monocytic cell lines induced a reduction in the growth of astrocytes and failed to induce productive infection. These in vitro observations support the hypothesis that astrocytes and glial cells may be a reservoir for HIV in the central nervous system and that macrophages may not carry the virus to the brain, but rather may be infected in the brain after having penetrated the blood-brain barrier.     

Dendritic cells: the host Achille's heel for mucosal pathogens?

Mucosal surfaces represent the main sites of interaction with environmental microorganisms and antigens. Sentinel cells, including epithelial cells and dendritic cells (DCs), continuously sense the environment and coordinate defenses for the protection of mucosal tissues. DCs play a central role in the control of adaptive immune responses owing to their capacity to internalize foreign materials, to migrate into lymph nodes and to present antigens to naive lymphocytes. Some pathogenic microorganisms trigger epithelial responses that result in the recruitment of DCs. These pathogens hijack the recruited DCs to enable them to infect the host, escape the host's defense mechanisms and establish niches at remote sites.     

Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS?

One strategy for the use of neural stem cells (NSCs) in treating neurological disorders is as transplantable "biological minipumps", in which genetically engineered neural stem cells serve as sources of secreted therapeutic (neuroprotective or tumoricidal) agents. Neural stem cells are highly mobile within the brain and demonstrate a tropism for various types of central nervous system (CNS) pathology, making them promising candidates for targeted gene delivery vehicles. Although neural stem cells have also been proposed as a potential source of replacement neurons and astrocytes to repopulate injured or degenerating neural circuits, the challenges involved in rebuilding damaged brain architecture are substantial and remain an active area of investigation. In contrast, the use of NSCs as biological minipumps does not rely on neuronal differentiation, axonal targeting, or synaptogenesis. This strategy may be a faster route to cell-based therapy of the CNS and is poised to move into human clinical trials. This review considers two types of neurologic disease that may be suitable targets for this alternative approach to NSC therapy: glial brain tumors and traumatic brain injury. We examine some of the key scientific and technical issues that must be addressed for the successful use of NSCs as minipumps.     

Stem cells for reprogramming: could hUMSCs be a better choice?

Human umbilical cord mesenchymal stem cells (hUMSC) are primitive multipotent cells capable of differentiating into cells of different lineages. They can be an alternative source of pluripotent cells since they are ethically and regulatory approved, are easily obtained and have low immunogenicity compared to embryonic stem cells which are dogged with numerous controversies. hUMSC can be a great source for cell and transplantation therapy.     

Artificial chromosomes: a blueprint for the future?

Recent developments in molecular genetics have led to the synthesis of an artificial human chromosome. Because the chromosome replicates and divides normally in human cells, this has exciting possibilities in terms of mankind's ability to influence evolutionary processes and to modify the human genome.     

Initiation of apoptosis in cells exposed to medium from the progeny of irradiated cells: a possible mechanism for bystander-induced genomic instability?

Genomic instability and bystander effects have recently been linked experimentally both in vivo and in vitro. The aim of the present study was to determine if medium from irradiated cells several passages distant from the original exposure could initiate apoptosis in unirradiated cells. Human keratinocytes (from the HPV-G cell line) were irradiated with 0.5 Gy or 5 Gy gamma rays. Medium was harvested at each passage up to the 7th passage (approximately 35 population doublings) postirradiation and transferred to unirradiated keratinocytes. Intracellular calcium levels, mitochondrial membrane potential, and the level of reactive oxygen species were all monitored for 24 h after medium transfer. Rapid calcium fluxes (within 30 s), loss of mitochondrial membrane potential, and increases in reactive oxygen species (from 6 h after medium transfer) were observed in the recipient cells. There was no significant difference between medium conditioned by cells irradiated with 0.5 or 5 Gy. The effect of medium from progeny was the same as the initial effect reported previously and did not diminish with increasing passage number. The data suggest that initiating events in the cascade that leads to apoptosis are induced in unirradiated cells by a signal produced by irradiated cells and that this signal can still be produced by the progeny of irradiated cells for several generations.     

Oct-1 functions as a transactivator in the hormonal induction of β-casein gene expression

An adverse environmental experience of the growing fetus leads to permanent changes in the structure and contractile function of the heart; however, the mechanisms are incompletely understood. To examine if a maternal low protein (LP) diet can modulate the gene and protein expression of the Ca²⁺-cycling proteins in the neonatal heart, we employed a rat model in which pregnant dams were fed diets containing either 180 (normal) or 90 g (low) casein/kg diet for 2 weeks before mating and throughout pregnancy. A significant reduction in the L-type Ca²⁺-channel mRNA level in the LP group was detected at 1, 7, and 14 days of age. Although ryanodine receptor (RyR) mRNA levels progressively declined in the aging heart in both groups, the RyR mRNA levels were consistently higher in the LP group. A reduction in RyR protein content was seen only in the hearts of the LP group at 7 days of age. The Na⁺-Ca²⁺-exchanger (NCX) mRNA level was also markedly increased at all ages. Although an increase in sarco(endo)plasmic reticulum ATPase 2a (SERCA) 2a mRNA was only detected in the LP group at 7 days of age, corresponding protein level was depressed. On the other hand, an initial decrease (at 1 day of age) followed by an increase (at 14 and 28 days of age) in phospholamban (PLB) mRNA levels was detected. Although PLB protein level was also depressed at 1 day of age in the LP group, a marked increase was seen at 7 days of age. Moreover, the ratio of serine 16 and threonine 17 phosphorylated PLB to non-phosphorylated PLB was reduced at 7 days of age in the hearts of offspring of the LP group. These data suggest that maternal LP diet can induce alterations in the gene expression and protein levels of the Ca²⁺-cycling proteins in the neonatal heart.     

Human umbilical cord blood cells: a new alternative for myocardial repair?

Cell therapy for myocardial disease is a rapidly progressive field. However, present strategies of cell transplantation into the infarcted myocardium have limitations from practical points of view. One of the biggest challenges is to achieve a sufficient number of suitable cells. Umbilical cord blood (UCB), an unlimited source of stem/progenitor cells that could be used for transplantation into the injured heart, is readily available. The aim of our review is to describe the potential and prospect of UCB as a new supplier of cells for myocardial repair. The use of UCB stem cells might be of importance to elderly and sick people in whom the availability of autologous stem cells is limited.