The CD3-Zeta Chimeric Antigen Receptor Overcomes TCR Hypo-Responsiveness of Human Terminal Late-Stage T Cells

Adoptive therapy of malignant diseases with tumor-specific cytotoxic T cells showed remarkable efficacy in recent trials. Repetitive T cell receptor (TCR) engagement of target antigen, however, inevitably ends up in hypo-responsive cells with terminally differentiated KLRG-1+ CD57+ CD7− phenotype limiting their therapeutic efficacy. We here revealed that hypo-responsiveness of CMV-specific late-stage CD8+ T cells is due to reduced TCR synapse formation compared to younger cells. Membrane anchoring of TCR components contributes to T cell hypo-responsiveness since dislocation of galectin-3 from the synapse by swainsonine restored both TCR synapse formation and T cell response. Transgenic expression of a CD3-zeta signaling chimeric antigen receptor (CAR) recovered hypo-responsive T cells to full effector functions indicating that the defect is restricted to TCR membrane components while synapse formation of the transgenic CAR was not blocked. CAR engineered late-stage T cells released cytokines and mediated redirected cytotoxicity as efficiently as younger effector T cells. Our data provide a rationale for TCR independent, CAR mediated activation in the adoptive cell therapy to avoid hypo-responsiveness of late-stage T cells upon repetitive antigen encounter

Fatty-Acid Preference Changes during Development in Drosophila melanogaster

Fatty-acids (FAs) are required in the diet of many animals throughout their life. However, the mechanisms involved in the perception of and preferences for dietary saturated and unsaturated FAs (SFAs and UFAs, respectively) remain poorly explored, especially in insects. Using the model species Drosophila melanogaster, we measured the responses of wild-type larvae and adults to pure SFAs (14, 16, and 18 carbons) and UFAs (C18 with 1, 2, or 3 double-bonds). Individual and group behavioral tests revealed different preferences in larvae and adults. Larvae preferred UFAs whereas SFAs tended to induce both a strong aversion and a persistent aggregation behavior. Adults generally preferred SFAs, and laid more eggs and had a longer life span when ingesting these substances as compared to UFAs. Our data suggest that insects can discriminate long-chain dietary FAs. The developmental change in preference shown by this species might reflect functional variation in use of FAs or stage-specific nutritional requirements, and may be fundamental for insect use of these major dietary components

Plant Diversity Surpasses Plant Functional Groups and Plant Productivity as Driver of Soil Biota in the Long Term

One of the most significant consequences of contemporary global change is the rapid decline of biodiversity in many ecosystems. Knowledge of the consequences of biodiversity loss in terrestrial ecosystems is largely restricted to single ecosystem functions. Impacts of key plant functional groups on soil biota are considered to be more important than those of plant diversity; however, current knowledge mainly relies on short-term experiments.We studied changes in the impacts of plant diversity and presence of key functional groups on soil biota by investigating the performance of soil microorganisms and soil fauna two, four and six years after the establishment of model grasslands. The results indicate that temporal changes of plant community effects depend on the trophic affiliation of soil animals: plant diversity effects on decomposers only occurred after six years, changed little in herbivores, but occurred in predators after two years. The results suggest that plant diversity, in terms of species and functional group richness, is the most important plant community property affecting soil biota, exceeding the relevance of plant above- and belowground productivity and the presence of key plant functional groups, i.e. grasses and legumes, with the relevance of the latter decreasing in time.Plant diversity effects on biota are not only due to the presence of key plant functional groups or plant productivity highlighting the importance of diverse and high-quality plant derived resources, and supporting the validity of the singular hypothesis for soil biota. Our results demonstrate that in the long term plant diversity essentially drives the performance of soil biota questioning the paradigm that belowground communities are not affected by plant diversity and reinforcing the importance of biodiversity for ecosystem functioning