Shaping the T-cell repertoire in the periphery

Selection of T cells does not end with events in the thymus, but continues in extrathymic tissues and for the life of the organism. In this review, we examine how self-reactive T cells are rendered harmless and the processes that select for T cells that are most efficient at combating pathogens. The implications of peripheral T-cell selection for the immune response as animals age are discussed as is the critical role of dendritic cells in directing T-cell differentiation.     

The importance of marine vs. human-induced subsidies in the maintenance of an expanding mesocarnivore in the arctic tundra

1. Most studies addressing the causes of the recent increases and expansions of mesopredators in many ecosystems have focused on the top-down, releasing effect of extinctions of large apex predators. However, in the case of the northward expansion of the red fox into the arctic tundra, a bottom-up effect of increased resource availability has been proposed, an effect that can counteract prey shortage in the low phase of the multi-annual rodent cycle. Resource subsidies both with marine and with terrestrial origins could potentially be involved. 2. During different phases of a multi-annual rodent cycle, we investigated the seasonal dynamics and spatial pattern of resource use by red foxes across a coast to inland low arctic tundra gradient, Varanger Peninsula, Norway. We employed two complementary methods of diet analyses: stomach contents and stable isotope analysis. 3. We found that inland red foxes primarily subsisted on reindeer carrions during the low phase of a small rodent population cycle. Lemmings became the most important food item towards the peak phase of the rodent cycle, despite being less abundant than sympatric voles. Isotopic signatures of tissue from both predator and prey also revealed that red foxes near the coast used marine-derived subsidies in the winter, but these allochthonous resources did not spillover to adult foxes living beyond 20-25 km from the coast. 4. Although more needs to be learned about the link between increasing primary productivity due to climatic warming and trophic dynamics in tundra ecosystems, we suggest that changes in reindeer management through a bottom-up effect, at least regionally, may have paved the way towards the establishment of a new mesopredator in the tundra biome.     

beta-Nerve growth factor participates in an auto/paracrine pathway of regulation of the meiotic differentiation of rat spermatocytes

NGF appears to be involved in spermatogenesis. However, mice lacking NGF or TrkA genes do not survive more than a few days whereas p75(NTR) knockout mice are viable and fertile. Therefore, we addressed the effect of betaNGF on spermatogenesis by using the systems of rat germ cell culture we established previously. betaNGF did not modify the number of Sertoli cells, pachytene spermatocytes, secondary spermatocytes nor the half-life of round spermatids, but increased the number of secondary meiotic metaphases and decreased the number of round spermatids formed in vitro. These effects of betaNGF were reversible and maximal at about 4 x 10(-11) M. Conversely, K252a, a Trk-specific kinase inhibitor, enhanced the number of round spermatids above that of control cultures. The presence of betaNGF and its receptors TrkA and p75(NTR) was investigated in testis sections, in Sertoli cell and germ cell fractions, and in germ cell and Sertoli cell co-cultures. betaNGF was detected only in germ cells from pachytene spermatocytes of stages VII up to spermatids of stages IX-X. TrkA and p75(NTR) were detected in Sertoli cells and in these germ cells. Taken together, these results indicate that betaNGF should participate in an auto/paracrine pathway of regulation of the second meiotic division of rat spermatocytes in vivo.     

Diet,nesting density,and breeding success of rough-legged buzzards (Buteo lagopus) on the Nenetsky Ridge,Arctic Russia

The rough-legged buzzard, a circumpolar avian predator, is usually defined as rodent specialist in the tundra but as a generalist in the boreal zone, leaving open the question of where the shift in feeding strategy occurs. Here, we investigated the diet and breeding biology of buzzards as well as abundance of their possible prey during 5 years in the low-Arctic shrub tundra on the Nenetsky Ridge, Russia. We employed three complementary methods to assess the diet of this Arctic predator—pellet dissection, identification of prey remains on nests, and stable isotope analysis—to overcome their respective limitations. We documented fluctuations in abundances of the likely prey, namely rodents, ptarmigans, and hares. Nesting density of buzzards changed substantially over the years, but did not track the abundance cycle of the rodents. The number of buzzard fledglings was relatively low (1.08 ± 0.3) and did not change according to the density of rodents. In the year when rodents were at their lowest abundance, diet analyses of nestlings documented a shift from rodents to alternative prey, with a decrease in the proportion of tundra voles and an increase in proportion of hares, ptarmigans, and ducks. Here, we argue that buzzards may adopt different feeding strategies along the gradient from generalists to specialists. While the rough-legged buzzard is usually considered a small rodent specialist, our study shows that it can shift to alternative prey where or when rodents are scarce and when alternative prey are sufficiently abundant to provide subsistence for breeding.     

Bird Communities of the Arctic Shrub Tundra of Yamal: Habitat Specialists and Generalists

Background

The ratio of habitat generalists to specialists in birds has been suggested as a good indicator of ecosystem changes due to e.g. climate change and other anthropogenic perturbations. Most studies focusing on this functional component of biodiversity originate, however, from temperate regions. The Eurasian Arctic tundra is currently experiencing an unprecedented combination of climate change, change in grazing pressure by domestic reindeer and growing human activity.

Methodology/Principal Findings

Here we monitored bird communities in a tundra landscape harbouring shrub and open habitats in order to analyse bird habitat relationships and quantify habitat specialization. We used ordination methods to analyse habitat associations and estimated the proportions of specialists in each of the main habitats. Correspondence Analysis identified three main bird communities, inhabiting upland, lowland and dense willow shrubs. We documented a stable structure of communities despite large multiannual variations of bird density (from 90 to 175 pairs/km²). Willow shrub thickets were a hotspot for bird density, but not for species richness. The thickets hosted many specialized species whose main distribution area was south of the tundra.

Conclusion/Significance

If current arctic changes result in a shrubification of the landscape as many studies suggested, we would expect an increase in the overall bird abundance together with an increase of local specialists, since they are associated with willow thickets. The majority of these species have a southern origin and their increase in abundance would represent a strengthening of the boreal component in the southern tundra, perhaps at the expense of species typical of the subarctic zone, which appear to be generalists within this zone.     

Evaluation of the human IgG antibody response to Aedes albopictus saliva as a new specific biomarker of exposure to vector bites

Background

The spread of Aedes albopictus, a vector for re-emergent arbovirus diseases like chikungunya and dengue, points up the need for better control strategies and new tools to evaluate transmission risk. Human antibody (Ab) responses to mosquito salivary proteins could represent a reliable biomarker for evaluating human-vector contact and the efficacy of control programs.

Methodology/Principal Findings

We used ELISA tests to evaluate specific immunoglobulin G (IgG) responses to salivary gland extracts (SGE) in adults exposed to Aedes albopictus in Reunion Island. The percentage of immune responders (88%) and levels of anti-SGE IgG Abs were high in exposed individuals. At an individual level, our results indicate heterogeneity of the exposure to Aedes albopictus bites. In addition, low-level immune cross-reactivity between Aedes albopictus and Aedes aegypti SGEs was observed, mainly in the highest responders.

Conclusion/Significance

Ab responses to saliva could be used as an immuno-epidemiological tool for evaluating exposure to Aedes albopictus bites. Combined with entomological and epidemiological methods, a “salivary” biomarker of exposure to Aedes albopictus could enhance surveillance of its spread and the risk of arbovirus transmission, and could be used as a direct tool for the evaluation of Aedes albopictus control strategies.     

Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12

We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p < 5 × 10(-8)) in our previous RA genome-wide association study (GWAS) were analyzed in independent sample sets consisting of 4,366 cases and 17,765 controls of European, African American, and East Asian ancestry. Additionally, we conducted an overall association test across all 65,833 samples (a GWAS meta-analysis plus the replication samples). Of the 13 SNPs investigated, four were significantly below the study-wide Bonferroni corrected p value threshold (p < 0.0038) in the replication samples. Two SNPs (rs3890745 at the 1p36 locus [p = 2.3 × 10(-12)] and rs2872507 at the 17q12 locus [p = 1.7 × 10(-9)]) surpassed genome-wide significance in all 16,659 RA cases and 49,174 controls combined. We used available GWAS data to fine map these two loci in Europeans and East Asians, and we found that the same allele conferred risk in both ethnic groups. A series of bioinformatic analyses identified TNFRSF14-MMEL1 at the 1p36 locus and IKZF3-ORMDL3-GSDMB at the 17q12 locus as the genes most likely associated with RA. These findings demonstrate empirically that a multiethnic approach is an effective strategy for discovering RA risk loci, and they suggest that combining GWASs across ethnic groups represents an efficient strategy for gaining statistical power.     

Mitochondrial Dysfunction in Lyssavirus-Induced Apoptosis

Lyssaviruses are highly neurotropic viruses associated with neuronal apoptosis. Previous observations have indicated that the matrix proteins (M) of some lyssaviruses induce strong neuronal apoptosis. However, the molecular mechanism(s) involved in this phenomenon is still unknown. We show that for Mokola virus (MOK), a lyssavirus of low pathogenicity, the M (M-MOK) targets mitochondria, disrupts the mitochondrial morphology, and induces apoptosis. Our analysis of truncated M-MOK mutants suggests that the information required for efficient mitochondrial targeting and dysfunction, as well as caspase-9 activation and apoptosis, is held between residues 46 and 110 of M-MOK. We used a yeast two-hybrid approach, a coimmunoprecipitation assay, and confocal microscopy to demonstrate that M-MOK physically associates with the subunit I of the cytochrome c (cyt-c) oxidase (CcO) of the mitochondrial respiratory chain; this is in contrast to the M of the highly pathogenic Thailand lyssavirus (M-THA). M-MOK expression induces a significant decrease in CcO activity, which is not the case with M-THA. M-MOK mutations (K77R and N81E) resulting in a similar sequence to M-THA at positions 77 and 81 annul cyt-c release and apoptosis and restore CcO activity. As expected, the reverse mutations, R77K and E81N, introduced in M-THA induce a phenotype similar to that due to M-MOK. These features indicate a novel mechanism for energy depletion during lyssavirus-induced apoptosis.During coevolution with their hosts, viruses have developed many ways of manipulating the cellular machinery of infected cells. They inhibit or induce apoptosis for their own benefit, with the purpose of increasing viral replication and spread or subverting the host''s immune response (4, 12, 51, 59).Mitochondria have several functions in the cell, including energy production, calcium buffering, and regulation of cellular apoptosis. Death signals in the intrinsic pathway of apoptosis act directly on mitochondria, leading to their dysfunction and the release of proapoptotic factors responsible for the caspase-dependent and/or -independent death pathways (43). The process is tightly regulated positively or negatively by proteins from the Bcl-2 family (32). Caspase activation can be initiated in the extrinsic pathway of apoptosis by death receptors expressed at the cell surface; this later causes mitochondrial dysfunction (8, 20).Lyssaviruses are highly neurotropic viruses associated with rabies, a fatal encephalomyelitis considered to be a reemerging zoonosis throughout most of the world (10). It has been suggested that lyssavirus-induced neuronal apoptosis (1), previously thought to be a principal cause of pathogenesis, is an important defense mechanism against lyssavirus infection (26, 34, 56). However, the molecular basis of lyssavirus-induced neuronal apoptosis is still poorly understood (16, 55). The involvement of the viral glycoprotein (G) in inducing neuronal apoptosis has been extensively shown (13, 38, 39, 45), whereas we have suggested that M is an inducer of neuronal cell death through a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent pathway (29). However, the molecular mechanism of apoptosis has not been precisely defined, and little is known about mitochondrial involvement during lyssavirus infections (46).In this study, we take advantage of the fact that Mokola virus (MOK), a member of the genotype 3 lyssaviruses (5), is known to be less pathogenic than viruses of genotype 1 and, in particular, Thailand virus (THA) (3). We report for the first time the involvement of the mitochondrial machinery during MOK-induced apoptosis. We show that the MOK matrix protein (M-MOK), a previously described apoptogenic factor (29), interacts directly with cytochrome c (cyt-c) oxidase (CcO) subunit I (CcO1), the terminal component of the mitochondrial respiratory chain (MRC). This finding is of interest, as this interaction, which is not found with M-THA, may have a key role in controlling ATP synthesis and cellular respiration during lyssavirus-induced neuronal apoptosis and may contribute to the low pathogenesis of MOK infection.