Exposure to inflammatory cytokines selectively limits GM-CSF production by induced T regulatory cells

Interest in manipulating the immunosuppressive powers of Foxp3-expressing T regulatory cells as an immunotherapy has been tempered by their reported ability to produce proinflammatory cytokines when manipulated in vitro, or in vivo. Understanding processes that can limit this potentially deleterious effect of Treg cells in a therapeutic setting is therefore important. Here, we have studied this using induced (i) Treg cells in which de novo Foxp3 expression is driven by TCR-stimulation in vitro in the presence of TGF-β. We show that iTreg cells can produce significant amounts of three proinflammatory cytokines (IFN-γ, GM-CSF and TNF-α) upon secondary TCR stimulation. GM-CSF is a critical T-cell derived cytokine for the induction of EAE in mice. Despite their apparent capacity to produce GM-CSF, myelin autoantigen-responsive iTreg cells were unable to provoke EAE. Instead, they maintained strong suppressive function in vivo, preventing EAE induction by their CD4+Foxp3− counterparts. We identified that although iTreg cells maintained the ability to produce IFN-γ and TNF-α in vivo, their ability to produce GM-CSF was selectively degraded upon antigen stimulation under inflammatory conditions. Furthermore, we show that IL-6 and IL-27 individually, or IL-2 and TGF-β in combination, can mediate the selective loss of GM-CSF production by iTreg cells

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4⁺ T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.</p> <p>Findings</p> <p>Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE.</p> <p>Conclusions</p> <p>DC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.</p

Crop Updates 2001 - Oilseeds

ABSTRACT This session covers twenty five papers from different authors: FORWARD, Mervyn McDougall, CHAIRMAN, PULSES AND OILSEEDS PARTNERSHIP GROUP PLENARY 1. Implications of the ‘green-bridge’ for viral and fungal disease carry-over between seasons, Debbie Thackray, Agriculture Western Australia and Centre for Legumes in Mediterranean Agriculture 2. Insect pest development in WA via the ‘green-bridge’, Kevin Walden, Agriculture Western Australia VARIETIES 3. Performance of new canola varieties in AGWEST variety trials, G. Walton, Crop Improvement Institute, Agriculture Western Australia 4. New herbicide tolerant varieties in WA, Kevin Morthorpe, Stephen Addenbrooke, Pioneer Hi-Bred Australia P/L 5. IT v’s TT – Head to head, Paul Carmody, Centre for Cropping Systems, Agriculture Western Australia ESTABLISHMENT 6. Effect of stubble, seeding technique and seed size on crop establishment and yield of canola, Rafiul Alam, Glen Riethmuller and Greg Hamilton, Agriculture Western Australia 7. Canola establishment survey 2000, Rafiul Alam, Paul Carmody, Greg Hamilton and Adrian Cox, Agriculture Western Australia 8. Tramline farming for more canola, Paul Blackwell, Agriculture Western Australia NUTRITION 9. Comparing the phosphorus requirement of canola and wheat in WA, M.D.A. Bolland and M.J. Baker, Agriculture Western Australia 10. Will a rainy summer affect nitrogen requirement: Tailoring your fertiliser decisions using the new nitrogen calculator, A.J. Diggle, Agriculture Western Australia 11. Canola – More response to lime, Chris Gazeyand Paul Carmody, Centre for Cropping Systems, Agriculture Western Australia AGRONOMY 12. Hormone manipulation of canola development, Paul Carmody and Graham Walton, Agriculture Western Australia 13. Yield penalties with delayed sewing of canola, Imma Farre, CSIRO Plant Industry, Michael J. Robertson, CSIRO Sustainable Ecosystems, Graham H. Walton, Agriculture Western Australia, Senthold Asseng, CSIRO Plant Industry 14. Dry matter and oil accumulation in developing seeds of canola varieties at different sowing dates, Ping Si1, David Turner1 and David Harris2 , 1Plant Sciences, Faculty of Agriculture, The University of Western Australia, 2Chemistry Centre of Western Australia 13. Simulating oil concentrations in canola – virtually just the beginning, David Turner1 and Imma Farré2, 1Plant Sciences, Faculty of Agriculture, The University of Western Australia, 2CSIRO Plant Industry, Centre for Mediterranean Agricultural Research PESTS AND DISEASES 14. Further evidence that canola crops are resilient to damage by aphids, Françoise Berlandier and Christiaan Valentine, Entomology, Agriculture Western Australia 15. Management of Diamondback moth (DBM) in canola, David Cook, Peter Mangano, David Cousins, Françoise Berlandier, and Darryl Hardie, Crop Improvement Institute,Agriculture Western Australia 16. Effect of time of sowing in conjunction with fungicides on blackleg and yield of canola, Ravjit Khangura and Martin Barbetti, Agriculture Western Australia 17. Further developments in forecasting aphid and virus risk in canola, Debbie Thackray, Jenny Hawkes and Roger Jones, Agriculture Western Australia and Centre for Legumes in Mediterranean Agriculture 18. Efficiency of selected insecticides for the use on Diamondback Moth in canola, Kevin Walden, Agriculture Western Australia 19. Impact® applied ‘in furrow’ controls blackleg in canola, Cameron Weeks and Erin Hasson, Mingenew-Irwin Group Inc. 20. Effect of time of sowing and Impact® on canola yield, Esperance, Dave Eksteen, Agriculture Western Australia 21. Australian Plague Locust Campaign 2000, Kevin Walden, Agriculture Western Australia WEED CONTROL 22. New herbicide options for canola, John Moore and Paul Matson, Agriculture Western Australia HARVESTING 23. Effects of time of swathing and desiccant application on the seed yield and oil content of canola, Carla Thomas and Lionel Martin, Muresk Institute of Agriculture, Curtin University of Technology DECISION SUPPORT AND ADOPTION 24. Using canola monitoring groups to understand factors affecting canola production in Esperance, Dave Eksteen, Agriculture Western Australia 25. Nitrogen and canola, Dave Eksteen, Agriculture Western Australi

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Cutting edge: IL-6-dependent autoimmune disease: dendritic cells as a sufficient, but transient, source

Mice lacking IL-6 are resistant to autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), which is driven by CNS-reactive CD4+ T cells. There are multiple cellular sources of IL-6, but the critical source in EAE has been uncertain. Using cell-specific IL-6 deficiency in models of EAE induced by active immunization, passive transfer, T cell transfer, and dendritic cell transfer, we show that neither the pathogenic T cells nor CNS-resident cells are required to produce IL-6. Instead, the requirement for IL-6 was restricted to the early stages of T cell activation and was entirely controlled by dendritic cell–derived IL-6. This reflected the loss of IL-6R expression by T cells over time. These data explain why blockade of IL-6R only achieves protection against EAE if used at the time of T cell priming. The implications for therapeutic manipulation of IL-6 signaling in human T cell–driven autoimmune conditions are considered

JOURNAL OF NEUROINFLAMMATION

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyeliti