The immunological synapse (IS) is a cell–cell junction formed between CD4+ T cells and dendritic cells (DCs). Here we show in vitro and in vivo that IS formation inhibits apoptosis of DCs. Consistent with these results, IS formation induced antiapoptotic signaling events, including activation of the kinase Akt1 and localization of the prosurvival transcription factor NF-kappaB and the proapoptotic transcription factor FOXO1 to the nucleus and cytoplasm, respectively. Inhibition of phosphatidylinositol 3-OH kinase and Akt1 partially prevented the antiapoptotic effects of IS formation. Direct stimulation of the IS component CD40 on DCs leads to the activation of Akt1, suggesting the involvement of this receptor in the antiapoptotic effects observed upon IS formation.

All three of this year’s recipients transformed the field of immunology with groundbreaking discoveries that led to a better understanding of how the human immune system senses and responds to infectious agents. Their subsequent scientific research has led to new therapies for people with infections, autoimmune disorders, and other immune system-related diseases. Dr. Beutler, Professor and Chairman of the department of genetics at Scripps Research Institute in La Jolla, CA, is famous for discovering several immune system proteins involved in sensing bacteria and viruses, and his subsequent development of therapies for patients. Dr. Beutler was born in Chicago in 1957, and grew up in Southern California. He graduated from the University of California, San Diego in 1976, and received his M.D. from the University of Chicago in 1981. He performed an internship and residency at the University of Texas Southwestern Medical Center, and was a postdoctoral fellow at Rockefeller University. Dr. Beutler was a professor and researcher at the University of Texas Southwestern Medical Center before joining the faculty at Scripps in 2000. Dr. Dinarello, Professor of Medicine at the University of Colorado Denver School of Medicine, is considered a founding father of cytokine biology, and his studies have focused on the immune system’s inflammatory reactions. He was born in 1943 in Boston. He received his medical degree from Yale University and performed a residency at Massachusetts General Hospital. In the 1970s, he was a clinical associate and senior investigator at the National Institutes of Health in Bethesda, MD. He was a professor of medicine and pediatrics at Tufts University School of Medicine and staff physician at New England Medical Center Hospital in Boston. He joined the faculty at the University of Colorado in 1996. Dr. Steinman, the Henry G. Kunkel Professor in Rockefeller University’s Laboratory of Cellular Physiology and Immunohematology in New York City, is world-renowned for his discovery and subsequent studies of the dendritic cell, the immune system’s central regulator. Born in Montreal in 1943, he graduated from McGill University in 1963, and earned his medical degree from Harvard Medical School in 1968. Following an internship and residency at Massachusetts General Hospital, he joined Rockefeller University in 1970 as a postdoctoral fellow. He was appointed an assistant professor in 1972, associate professor in 1976, and professor in 1988. He was named Henry G. Kunkel Professor in 1995 and director of the Christopher H. Browne Center for Immunology and Immune Diseases in 1998.

The nation's richest prize in medicine and biomedical research was awarded Friday to three immune system researchers for work that led to new treatments for rheumatoid arthritis and diabetes. The $500,000 Albany Medical Center Prize is being shared by Dr. Ralph Steinman of Rockefeller University, Dr. Charles Dinarello, of the University of Colorado, and Dr. Bruce Beutler, of The Scripps Research Institute in La Jolla, Calif. It's the largest medicine or science award in the United States, and ranks second only to the $1.4 million Nobel Prize among medical prizes.

For the efficient stimulation of T cells by tumor Ag, tumor-derived material has to be presented by dendritic cells (DC). This very likely involves the uptake of dead tumor cells by DC. Cell death in tumors often occurs through apoptosis, but necrotic cell death may also be prevalent. This distinction is relevant because numerous studies have proposed that apoptotic cells have immunosuppressive effects while necrosis may be stimulatory. However, a system has been lacking that would allow the induction of apoptosis or necrosis without side effects by the death stimuli used experimentally. In this study, we present such a system and test its effects on immune cells in vitro. B16 mouse melanoma cells were generated and underwent cell death through the doxycycline-inducible induction of death proteins. In one cell line, the induction of Bim(S) induced rapid apoptosis, in the other line the induction of the FADD death domain induced nonapoptotic/necrotic cell death. Bim(S)-induced apoptosis was associated with the typical morphological and biochemical changes. FADD death domain induced necrosis occurred through a distinct pathway involving RIP1 and the loss of membrane integrity in the absence of apoptotic changes. Apoptotic and necrotic cells were taken up with comparable efficiency by DC. OVA expressed in cells dying by either apoptosis or necrosis was cross-presented to OT-1 T cells and induced their proliferation. These results argue that it is not the form of cell death but its circumstances that decide the question whether cell death leads to a productive T cell response.

Injury or impaired clearance of apoptotic cells leads to the pathological accumulation of necrotic corpses, which induce an inflammatory response that initiates tissue repair1. In addition, antigens present in necrotic cells can sometimes provoke a specific immune response2, 3, 4 and it has been argued that necrosis could explain adaptive immunity in seemingly infection-free situations, such as after allograft transplantation or in spontaneous and therapy-induced tumour rejection5, 6. In the mouse, the CD8alpha+ subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8+ T cells against cell-associated antigens7. Here we show that CD8alpha+ dendritic cells use CLEC9A (also known as DNGR-1), a recently-characterized C-type lectin8, 9, 10, to recognize a preformed signal that is exposed on necrotic cells. Loss or blockade of CLEC9A does not impair the uptake of necrotic cell material by CD8alpha+ dendritic cells, but specifically reduces cross-presentation of dead-cell-associated antigens in vitro and decreases the immunogenicity of necrotic cells in vivo. The function of CLEC9A requires a key tyrosine residue in its intracellular tail that allows the recruitment and activation of the tyrosine kinase SYK, which is also essential for cross-presentation of dead-cell-associated antigens. Thus, CLEC9A functions as a SYK-coupled C-type lectin receptor to mediate sensing of necrosis by the principal dendritic-cell subset involved in regulating cross-priming to cell-associated antigens.

Leukocidin (Luk), an exotoxin of Staphylococcus aureus consisting of LukF and LukS, is a hetero-oligomeric pore-forming cytolytic toxin toward human and rabbit polymorphonuclear leukocytes. However, it is uncertain how Luk affects the host immune response. In the present study, we investigated whether Luk has the ability to stimulate mouse bone marrow-derived myeloid dendritic cells (BM-DCs). LukF activated BM-DCs to generate IL-12p40 mRNA, induce intracellular expression and extracellular secretion of this cytokine and express CD40 on their surface, whereas LukS showed a much lower or marginal ability in the activation of BM-DCs than its counterpart component. Similarly, TNF-alpha was secreted by BM-DCs upon stimulation with these components. Combined addition of these components did not lead to a further increase in IL-12p40 secretion. IL-12p40 production caused by LukF was completely abrogated in BM-DCs from TLR4-deficient mice similarly to the response to lipopolysaccharide (LPS). Polymixin B did not affect the LukF-induced IL-12p40 production, although the same treatment completely inhibited the LPS-induced response. Boiling significantly inhibited the response caused by LukF, but not by LPS. Finally, in a luciferase reporter assay, LukF induced the activation of NF-kappaB in HEK293FT cells transfected with TLR4, MD2 and CD14, whereas LukS did not show such activity. These results demonstrate that LukF caused the activation of BM-DCs by triggering a TLR4-dependent signaling pathway and suggests that Luk may affect the host inflammatory response as well as show a cytolytic effect on leukocytes.