An early history of T cell-mediated cytotoxicity.

After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications

Climate change effects on winter chill for tree crops with chilling requirements on the Arabian Peninsula

Fruit production systems that rely on winter chill for breaking of dormancy might be vulnerable to climatic change. We investigated decreases in the number of winter chilling hours (0–7.2°C) in four mountain oases of Oman, a marginal area for the production of fruit trees with chilling requirements. Winter chill was calculated from long-term hourly temperature records. These were generated based on the correlation of hourly temperature measurements in the oases with daylength and daily minimum and maximum temperatures recorded at a nearby weather station. Winter chill was estimated for historic temperature records between 1983 and 2008, as well as for three sets of synthetic 100-year weather records, generated to represent historic conditions, and climatic changes likely to occur within the next 30 years (temperatures elevated by 1°C and 2°C). Our analysis detected a decrease in the numbers of chilling hours in high-elevation oases by an average of 1.2–9.5 h/year between 1983 and 2008, a period during which, according to the scenario analysis, winter chill was sufficient for most important species in most years in the highest oasis. In the two climate change scenarios, pomegranates, the most important tree crop, received insufficient chilling in 13% and 75% of years, respectively. While production of most traditional fruit trees is marginal today, with trees barely fulfilling their chilling requirements, such production might become impossible in the near future. Similar developments are likely to affect other fruit production regions around the world

Cross-linking of neutrophil CD11b results in rapid cell surface expression of molecules required for antigen presentation and T-cell activation

Recent studies suggest that neutrophils may play a role in antigen presentation. In support of this hypothesis it has been shown that these cells appear to contain cytoplasmic stores of molecules required for this function, i.e. major histocompatibility complex class II (DR) antigen, CD80 and CD86. In this study we have considered a mechanism for the translocation of these preformed molecules onto the cell surface which does not require active synthesis. Cross-linking of the Mac-1 molecule (CD18 + CD11b) was shown to result in rapid cell surface expression of CD80, CD86 and DR antigen on the surface of normal human peripheral blood neutrophils. A distinct subpopulation (approximately 20%) of neutrophils appeared to be enlarged and were found to express significantly elevated levels of these molecules on the cell surface following cross-linking of CD11b when compared with control cells. The level of expression of CD80, CD86 and DR antigen on these large cells was comparable to, and in some cases greater than, the levels found expressed on the surface of monocytes obtained from the same donors. In addition, these cytoplasmic molecules were shown by confocal laser microscopy and by immunoelectron microscopy to be located within secretory vesicles. Following rapid translocation onto the cell surface, CD80 and CD86 appeared to be colocalized within large clusters reminiscent of the supramolecular antigen clusters previously found on conventional antigen-presenting cells. These findings therefore lend further support for the hypothesis that neutrophils may have a role to play in antigen presentation and/or T-cell activation

Enhanced expression of CTLA-4 (CD152) on CD4+ T cells in HIV infection

CTLA-4 (CD152) is a surface molecule of activated T cells with sequence homology to CD28. Both molecules bind to the same ligands, B7.1 (CD80) and B7.2 (CD86) but have antagonistic functions. While CD28 is an important costimulator, CTLA-4 has an essential inhibitory function in maintaining the homeostasis of the immune system. Down- regulation of CD28 predominantly on CD8+ T cells has been described in HIV infection, but analysis of CTLA-4 is complicated by its low expression levels. Here we have used potent signal enhancement to study CTLA-4 on peripheral blood mononuclear cells (PBMC) during HIV infection. CTLA-4 was expressed only on T cells. Expression levels were significantly increased selectively on CD4+ T cells during all stages of HIV infection, while CTLA-4 expression on CD8+ T cells was always low. In contrast, after stimulation with the mitogen phytohaemagglutinin (PHA), CTLA-4 levels were strongly increased on T cells from controls but in T cells from HIV patients this response was severely impaired. Our data suggest that in HIV infection CD4+ and CD8+ T cells may be less responsive to B7 costimuli due to two different mechanisms: increase in CTLA-4 expression by CD4+ cells and down-regulation of CD28 by CD8+ cells

Climate change effects on winter chill for fruit crops in Germany

To quantify the effects of climate change on fruit production in Germany, this study aimed at determining long-term trends in winter chill, as calculated with the Chilling Hours and Dynamic Models (Chill Portions). An idealized daily temperature curve was used to convert daily temperature records from 43 weather stations, taken throughout the twentieth and late nineteenth centuries, into an hourly dataset, which was then converted to units of winter chill. Besides exposing temporal trends in winter chill, the data could be spatially interpolated, yielding contiguous maps of typical winter chill in Germany around 2010, as well as chilling losses since 1950. Throughout Germany, winter chill varied between 1700 and 3000 Chilling Hours or 125 and 150 Chill Portions. The areas of highest winter chill were located in the northern parts of the country. For the whole of Germany, there were no significant temporal trends. The extent of interregional variation in winter chill depended on the chilling model used. While the Chilling Hours Model showed strong declines in winter chill for the areas around Dresden and Leipzig, as well as for the Lake Constance region, the Dynamic Model did not detect such dramatic changes. More than a decline in winter chill, increased heat during the winter months might become a challenge to German fruit growers. As already experienced during the extraordinarily warm winter of 2006/07, warm temperatures during the winter can cause fruit trees that fulfill their chilling requirements relatively early to bloom prematurely. This can then lead to elevated risk of frost damage and hamper the homogeneity of flowering