Jessica Fanzo

Modulation of T Cell Cytokine Production by Interferon Regulatory Factor-4

Production of cytokines is one of the major mechanisms employed by CD4+ T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4+ T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines.

Understanding Sustainable Diets: A Descriptive Analysis of the Determinants and Processes That Influence Diets and Their Impact on Health, Food Security, and Environmental Sustainability

The confluence of population, economic development, and environmental pressures resulting from increased globalization and industrialization reveal an increasingly resource-constrained world in which predictions point to the need to do more with less and in a “better” way. The concept of sustainable diets presents an opportunity to successfully advance commitments to sustainable development and the elimination of poverty, food and nutrition insecurity, and poor health outcomes. This study examines the determinants of sustainable diets, offers a descriptive analysis of these areas, and presents a causal model and framework from which to build. The major determinants of sustainable diets fall into 5 categories: 1) agriculture, 2) health, 3) sociocultural, 4) environmental, and 5) socioeconomic. When factors or processes are changed in 1 determinant category, such changes affect other determinant categories and, in turn, the level of “sustainability” of a diet. The complex web of determinants of sustainable diets makes it challenging for policymakers to understand the benefits and considerations for promoting, processing, and consuming such diets. To advance this work, better measurements and indicators must be developed to assess the impact of the various determinants on the sustainability of a diet and the tradeoffs associated with any recommendations aimed at increasing the sustainability of our food system.

Loss of IRF-4–binding protein leads to the spontaneous development of systemic autoimmunity

IFN regulatory factor 4-binding (IRF-4-binding) protein (IBP) is a novel type of activator of Rho GTPases that is recruited to the immunological synapse upon TCR stimulation. Here we demonstrate that loss of IBP leads to the spontaneous development of a systemic autoimmune disorder characterized by the accumulation of effector/memory T cells and IgG+ B cells, profound hypergammaglobulinemia, and autoantibody production. Similar to human SLE, this syndrome primarily affects females. T cells from IBP-deficient mice are resistant to death in vitro as well as in vivo and exhibit selective defects in effector function. In the absence of IBP, T cells respond suboptimally to TCR engagement, as demonstrated by diminished ERK1/2 activation, decreased c-Fos induction, impaired immunological synapse formation, and defective actin polymerization. Transduction of IBP-deficient T cells with a WT IBP protein, but not with an IBP mutant lacking the Dbl-like domain required for Rho GTPase activation, rescues the cytoskeletal defects exhibited by these cells. Collectively, these findings indicate that IBP, a novel regulator of Rho GTPases, is required for optimal T cell effector function, lymphocyte homeostasis, and the prevention of systemic autoimmunity.

Integrating a broader notion of food security and gender empowerment into the African Green Revolution

A Green Revolution for Africa is emerging after decades of neglect of Africa’s agricultural systems. To counter these years of neglect, the then United Nations Secretary-General Kofi Annan called for “a uniquely African Green Revolution”. Since then, a number of initiatives have emerged or are emerging to realize this important vision. As more money and attention galvanizes much-needed action on the African Green Revolution, a vigorous debate is required to ensure that the mission of improving food security on the world’s poorest continent is achieved in the most effective, comprehensive and inclusive manner possible. The African Green Revolution cannot be limited to increasing yields of staple crops but must be designed as a driver of sustainable development, which includes gender empowerment and nutrition elements. This paper first reviews the Asian Green Revolution’s successes and shortcomings from a nutrition and gender perspective and then outlines what the global community can do to ensure that some of the limitations of the Asian Green Revolution, specifically with regard to nutrition and gender, are not repeated.

CD95 Rapidly Clusters in Cells of Diverse Origins

We have shown that CD95-mediated cell death requires a clustering of the receptor in distinct sphingolipid-rich domains of the cell membrane (Grassmé et al., 2000, Cremesti et al., 2000). These domains form in response to acid sphingomyelinase (ASM)-induced ceramide generation. However, recent studies challenged the finding of early CD95 clustering (Algeciras-Schimnich et al., 2002). Here, six independent groups tested clustering of CD95 in diverse cell type including primary cells ex vivo and established cell lines. The studies show clustering of CD95 within seconds to minutes in all cell types tested by the different groups. In addition, clustering of CD95 was detected after stimulation of cells using three agonistic anti-CD95 antibodies (CH11, APO-1-3 and JO2), CD95 ligand and stimuli that induce an upregulation and activation of the endogenous CD95/CD95 ligand system. The data confirm our previous studies and suggest rapid, i.e. within seconds to minutes, CD95 clustering as a general phenomenon occurring in many cell types.

Metrics for land-scarce agriculture

Nutrient content must be better integrated into planning Over the past half-century, the paradigm for agricultural development has been to maximize yields through intensifying production, particularly for cereal crops (1). Increasing production of high-yielding cereals—wheat, rice, and maize—has replaced more nutrient-rich cereals, which has eroded the content of essential dietary nutrients in the worlds cereal supply. New approaches are needed to produce healthy foods, rich in essential nutrients, with efficient use of land. Standard yield metrics that measure the quantity of production are inadequate to assess progress toward this goal; thus, we propose alternative metrics of nutritional yields.

Production and supply of high‐quality food protein for human consumption: sustainability, challenges, and innovations

The Food and Agriculture Organization of the United Nations estimates that 843 million people worldwide are hungry and a greater number suffer from nutrient deficiencies. Approximately one billion people have inadequate protein intake. The challenge of preventing hunger and malnutrition will become even greater as the global population grows from the current 7.2 billion people to 9.6 billion by 2050. With increases in income, population, and demand for more nutrient‐dense foods, global meat production is projected to increase by 206 million tons per year during the next 35 years. These changes in population and dietary practices have led to a tremendous rise in the demand for food protein, especially animal‐source protein. Consuming the required amounts of protein is fundamental to human growth and health. Protein needs can be met through intakes of animal and plant‐source foods. Increased consumption of food proteins is associated with increased greenhouse gas emissions and overutilization of water. Consequently, concerns exist regarding impacts of agricultural production, processing and distribution of food protein on the environment, ecosystem, and sustainability. To address these challenging issues, the New York Academy of Sciences organized the conference “Frontiers in Agricultural Sustainability: Studying the Protein Supply Chain to Improve Dietary Quality” to explore sustainable innovations in food science and programming aimed at producing the required quality and quantity of protein through improved supply chains worldwide. This report provides an extensive discussion of these issues and summaries of the presentations from the conference.

Multisector intervention to accelerate reductions in child stunting: an observational study from 9 sub-Saharan African countries

BACKGROUND In sub-Saharan Africa, ~ 40% of children <5 y old are stunted, with levels that have remained largely unchanged over the past 2 decades. Although the complex determinants of undernutrition are well recognized, few studies have evaluated strategies that combine nutrition-specific, health-based approaches with food system- and livelihood-based interventions. OBJECTIVE We examined changes in childhood stunting and its determinants after 3 y of exposure to an integrated, multisector intervention and compared these changes with national trends. DESIGN A prospective observational trial was conducted across rural sites in 9 sub-Saharan African countries with baseline levels of childhood stunting >20%. A stratified random sample of households and resident children <2 y old from villages exposed to the program were enrolled in the study. Main outcome measures included principal determinants of undernutrition and childhood stunting, which was defined as a height-for-age z score less than -2. National trends in stunting were generated from demographic and health surveys. RESULTS Three years after the start of the program in 2005-2006, consistent improvements were observed in household food security and diet diversity, whereas coverage with child care and disease-control interventions improved for most outcomes. The prevalence of stunting in children <2 y old at year 3 of the program (2008-2009) was 43% lower (adjusted OR: 0.57; 95% CI: 0.38, 0.83) than at baseline. The average national stunting prevalence for the countries included in the study had remained largely unchanged over the past 2 decades. CONCLUSION These findings provide encouraging evidence that a package of multisector interventions has the potential to produce reductions in childhood stunting.

Ecological Approaches to Human Nutrition

Background Malnutrition affects a large number of people throughout the developing world. Approaches to reducing malnutrition rarely focus on ecology and agriculture to simultaneously improve human nutrition and environmental sustainability. However, evidence suggests that interdisciplinary approaches that combine the knowledge bases of these disciplines can serve as a central strategy in alleviating hidden hunger for the worlds poorest. Objective To describe the role that ecological knowledge plays in alleviating hidden hunger, considering human nutrition as an overlooked ecosystem service. Methods We review existing literature and propose a framework that expands on earlier work on econutrition. We provide novel evidence from case studies conducted by the authors in western Kenya and propose a framework for interdisciplinary collaboration to alleviate hidden hunger, increase agricultural productivity, and improve environmental sustainability. Results Our review supports the concept that an integrated approach will impact human nutrition. We provide evidence that increased functional agrobiodiversity can alleviate anemia, and interventions that contribute to environmental sustainability can have both direct and indirect effects on human health and nutritional well-being. Conclusions Integrated and interdisciplinary approaches are critical to reaching development goals. Ecologists must begin to consider not only how their field can contribute to biodiversity conservation, but also, the relationship between biodiversity and provisioning of nontraditional ecosystem services such as human health. Likewise, nutritionists and agronomists must recognize that many of the solutions to increasing human well-being and health can best be achieved by focusing on a healthy environment and the conservation of ecosystem services.

Regulation of Lymphocyte Apoptosis by Interferon Regulatory Factor 4 (IRF-4)

To ensure that homeostasis of the immune system is maintained, the sensitivity of lymphocytes to Fas-mediated apoptosis is differentially regulated during their activation. The molecular mechanisms that link the activation program of lymphocytes to changes in sensitivity to Fas-mediated apoptosis have, however, not been fully characterized. In these studies, we have investigated whether Fas-mediated apoptosis can be regulated by interferon regulatory factor 4 (IRF-4), a lymphoid-restricted member of the IRF family of transcription factors. IRF-4 expression is upregulated during lymphocyte activation and IRF-4–deficient mice have defects in both lymphocyte activation and homeostasis. Here, we show that stable expression of IRF-4 in a human lymphoid cell line that normally lacks IRF-4 leads to a significantly enhanced apoptotic response on Fas receptor engagement. A systematic examination of the downstream effectors of Fas signaling in IRF-4–transfected cells demonstrates an increased activation of caspase-8, as well as an increase in Fas receptor polarization. We demonstrate that IRF-4–deficient mice display defects in activation-induced cell death, as well as superantigen-induced deletion, and that these defects are accompanied by impairments in Fas receptor polarization. These data suggest that IRF-4, by modulating the efficiency of the Fas-mediated death signal, is a novel participant in the regulation of lymphoid cell apoptosis.