A role for the granzyme B inhibitor serine protease inhibitor 6 in CD8+ memory cell homeostasis

Generation and maintenance of protective immunological memory is the goal of vaccination programs. It has recently become clear that CD8+ memory T cells are derived directly from CTLs. The mechanisms underlying this transformation and the subsequent survival of memory cells are not completely understood. However, some effector molecules required by CTLs to eliminate infected cells have also been shown to control the number of Ag-specific cells. We report that memory cells express high levels of serine protease inhibitor (Spi) 6, an inhibitor of the effector molecule granzyme B, and that Spi6 can protect T cells from granzyme B-mediated apoptosis. In mouse models, both elevated expression of Spi6 and the complete absence of granzyme B in CD8+ T cells led to an increase in memory cells after infection with lymphocytic choriomeningitis virus. This was not the result of increased levels of antilymphocytic choriomeningitis virus CD8+ T cells during the expansion or contraction phases, but rather transgenic Spi6 directly influenced the survival of CD8+ memory T cells. We propose that expression of protective molecules, like Spi6, serves to shield metabolically active CD8+ memory T cells from their own effector molecules.     

How choosy should I be? The relative searching time predicts evolution of choosiness under direct sexual selection

Most theoretical research in sexual selection has focused on indirect selection. However, empirical studies have not strongly supported indirect selection. A well-established finding is that direct benefits and costs exert a strong influence on the evolution of mate choice. We present an analytical model in which unilateral mate choice evolves solely by direct sexual selection on choosiness. We show this is sufficient to generate the evolution of all possible levels of choosiness, because of the fundamental trade-off between mating rate and mating benefits. We further identify the relative searching time (RST, i.e. the proportion of lifetime devoted to searching for mates) as a predictor of the effect of any variable affecting the mating rate on the evolution of choosiness. We show that the RST: (i) allows one to make predictions about the evolution of choosiness across a wide variety of mating systems; (ii) encompasses all alternative variables proposed thus far to explain the evolution of choosiness by direct sexual selection; and (iii) can be empirically used to infer qualitative differences in choosiness.     

A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy

Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCas^E murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies.     

Reshaping of bulbar odor response by nasal flow rate in the rat

Background

The impact of respiratory dynamics on odor response has been poorly studied at the olfactory bulb level. However, it has been shown that sniffing in the behaving rodent is highly dynamic and varies both in frequency and flow rate. Bulbar odor response could vary with these sniffing parameter variations. Consequently, it is necessary to understand how nasal airflow can modify and shape odor response at the olfactory bulb level.

Methodology and Principal Findings

To assess this question, we used a double cannulation and simulated nasal airflow protocol on anesthetized rats to uncouple nasal airflow from animal respiration. Both mitral/tufted cell extracellular unit activity and local field potentials (LFPs) were recorded. We found that airflow changes in the normal range were sufficient to substantially reorganize the response of the olfactory bulb. In particular, cellular odor-evoked activities, LFP oscillations and spike phase-locking to LFPs were strongly modified by nasal flow rate.

Conclusion

Our results indicate the importance of reconsidering the notion of odor coding as odor response at the bulbar level is ceaselessly modified by respiratory dynamics.     

Faster, deeper, better: the impact of sniffing modulation on bulbar olfactory processing

A key feature of mammalian olfactory perception is that sensory input is intimately related to respiration. Different authors have considered respiratory dynamics not only as a simple vector for odor molecules but also as an integral part of olfactory perception. Thus, rats adapt their sniffing strategy, both in frequency and flow rate, when performing odor-related tasks. The question of how frequency and flow rate jointly impact the spatio-temporal representation of odor in the olfactory bulb (OB) has not yet been answered. In the present paper, we addressed this question using a simulated nasal airflow protocol on anesthetized rats combined with voltage-sensitive dye imaging (VSDi) of odor-evoked OB glomerular maps. Glomerular responses displayed a tonic component during odor stimulation with a superimposed phasic component phase-locked to the sampling pattern. We showed that a high sniffing frequency (10 Hz) retained the ability to shape OB activity and that the tonic and phasic components of the VSDi responses were dependent on flow rate and inspiration volume, respectively. Both sniffing parameters jointly affected OB responses to odor such that the reduced activity level induced by a frequency increase was compensated by an increased flow rate.