| Laboratory of Immunology |
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| Dennis D. Taub, Ph.D., Investigator Chief, Clinical Immunology Section and Chief (Acting) Laboratory of Immunology |
 Dr. Dennis D. Taub received his Ph.D. from the Department of Microbiology and Immunology at Temple University School of Medicine in Philadelphia in 1991. He subsequently entered the laboratory of Dr. Joost J. Oppenheim as a staff fellow at the National Cancer Institute in Frederick, Maryland. From 1994-1997, Dr. Taub headed the vaccine monitoring laboratory within the Clinical Services Program at the National Cancer Institute. In early 1997, he moved to the Laboratory of Immunology at the National Institute on Aging as the Chief of the Clinical Immunology Section and the Acting Chief of the Laboratory of Immunology. Research Interests: Chemokines, Aging, and Immune Responses: The recruitment of lymphocytes into inflammatory sites requires several activation events including endothelial cell activation by inflammatory cytokines, the expression of adhesion molecules, cellular adhesion, diapedesis, and migration via established chemotactic gradients. Over the past 10 years, members of the chemokine super family have been shown to induce adhesion, chemotaxis, activation, and degranulation of human and rodent leukocytes and lymphocytes both in vitro and in vivo. We are currently examining a role for chemokines in lymphocyte activation and as immunodjuvants in vaccine-based studies with hapten-carrier protein complexes. In addition, the laboratory is also examining the ability of various chemokines and other G-protein receptor ligands to modulate other T, B, and NK cell effector functions as well as antigen-presenting cell activities. Furthermore, studies examining the differential expression of various cytokines, chemokines and their cell surface receptors, post cellular activation via mitogens, hormones, lipids, and stress factors are also under investigation. As no cytokines or chemokines are ever alone within an inflammatory site, it is critical to determine how these various growth factors influence each others' signals and functions. Using purified rodent, primate, and human immune cell subsets, we have observed a significant dampening of aged lymphocyte and mononuclear cell migration, adhesion, and chemokine receptor signaling in response to ligand stimulation compared to younger control populations. The age-related changes that appear to play a role in this chemokine hyporesponsiveness include signaling defects through cell surface receptors, differences in cell surface receptor expression after cellular activation, and preferential expression or lack of expression of certain chemokine receptors on circulating immune subsets within an aged host. We believe that a better understanding of the complexities of leukocyte extravasation and the mediators that induce cell trafficking and activation will greatly assist our ability to orchestrate, regulate, and control various pathological disease states associated with aging as well as enhance our understanding of normal leukocyte trafficking. |
| Cholesterol and Lipid Rafts in T Lymphocyte Signaling and Trafficking: Relevance to Aging and Inflammatory Disease: Chemokine receptors (CRs) have drawn much attention since their description as human immunodeficiency virus (HIV) co-receptors by several groups in 1996. Before that time, HIV tropism was defined as either macrophage (M)- or T cell (T)-tropic, which corresponded to non-syncytia- or syncytia-inducing viruses, respectively. Today, the classification of HIV tropism is defined by chemokine receptor usage of CCR5, CXCR4, or both receptors. Certain CRs have been shown to be palmitoylated and targeted to cholesterol-and sphingolipid-rich membrane microdomains termed lipid rafts. Lipid rafts is a broad term describing membrane microdomains enriched in cholesterol, sphingolipids, glycosylphosphatidylinositol-anchored proteins, and acylated signaling molecules on the plasma membrane of immune and non-immune cells. These rafts are believed to be important signaling platforms as well as sites of assembly for the TCR signaling complex. One of the most crucial components in maintaining the higher lipid order of rafts is cholesterol, and extraction of cholesterol by cyclodextrins (circular multimeric sugars), disrupts lipid rafts and increases overall membrane fluidity. The removal of cholesterol has profound effects on the ability of several GPCRs to bind their ligand. In addition, direct oxidation of cholesterol within the plasma membrane or treatment of cells with oxidized cholesterols called "oxysterols" also inhibits chemokine binding and activity as well as HIV-1 infectivity. Moreover, the cholesterol balance appears to be quite strict as the continued addition of cholesterol to the T cell membranes also inhibits chemokine receptor function and T cell activation. Finally, we have explored the ability of TCR or CD4 engagement to mediate adhesion molecule, chemokine receptor, and cholesterol colocalization and found that colocalization is dependent on the presence of cellular cholesterol, cytoskeletal reorganization, and lck signaling. These cell surface rearrangements that result in the capping of chemokine receptors, adhesion molecules, and lipid rafts to the site of CD4 contact may serve as a mechanism for HIV propagation and pathogenesis. Our current findings provide insight into the role of cholesterol and oxidized cholesterols in chemokine receptor structure and function. More specific efforts are also underway examining the differences in the make-up of lipid rafts within the cell membranes of young and aged lymphocytes. Given the large number of alterations in lipid peroxidation and metabolism with age, changes in the types, saturation and levels of various membrane sphingolipids, fatty acids and cholesterol may result in specific changes in membrane fluidity, protein association and aggregation, cellular activation and function. We believe that a greater understanding of the various signaling and cell surface proteins associated with lipid rafts may provide great insight into age-related alterations in cell signaling and migration. |
| Novel Connections Between the Immune and Endocrine Systems: Inflammatory cytokines released by immune cells have been shown to act on the central nervous system (CNS) to control food intake and energy homeostasis. Decrease in food intake or anorexia is one of the most common symptoms of illness, injury or inflammation. The adipocyte-derived hormone, leptin, is considered a critical sensory anorexigenic mediator that signals to the brain changes in stored energy, determined by an altered balance between food intake and energy expenditure and has been shown to exert certain proinflammatory effects on immune cells. In contrast, ghrelin, the endogenous ligand for growth hormone secretagogue receptors (GHS-R), is produced primarily from stomach serving as a potent circulating orexigen controlling energy expenditure, adiposity and GH secretion. However, the functional role of ghrelin and GHS in immune cell function is unknown. Here, we report that GHS-R and ghrelin are expressed in human T lymphocytes, specifically localize in lipid rafts, exerts both specific and potent inhibitory effects on the TCR- and leptin-mediated expression of the proinflammatory cytokines via functional GHS-R and possible a novel GHS receptor on the surface of human mononuclear and T cells. Moreover, ghrelin administration into endotoxin challenged mice significantly inhibits inflammatory cytokine mRNA expression in the spleen, liver and lungs as well as serum cytokine levels. Furthermore, the expression of ghrelin, leptin and their receptors as well as GH appear to be significantly diminished with age within specific immune subsets and lymphoid organs, including the thymus. Administration of ghrelin and leptin to aged mice using implanted osmotic pumps resulted in a reversal of thymic involution and restored thymic GH expression. Our laboratory and others have demonstrated that the hormones, prolactin, GH and IGF1 potentiate human and rodent lymphocyte activation and proliferation in response to various antigens and stimuli both in vitro and in vivo. These hormones have also been shown to modulate a variety of leukocyte functions including potentiating lymphocyte activation and thymic engraftment and regeneration. Together, these data support the existence of a functional immunoregulatory network playing a significant role in cytokine regulation, cellular activation and survival. These data also support the potential therapeutic use of ghrelin and GHS-R agonists in the management of wasting associated with chronic inflammation and cancer and in restoration of thymic function in immunocompromised individuals. |
| Molecular and Biological Mechanisms of Age-associated Thymic Involution: One of the consequences of an aging immune system is the process of thymic involution. The thymus undergoes a progressive reduction in size due to profound changes in its architecture associated with thymic epithelia atrophy and decreased thymopoiesis. This decline is systemically followed by decreased numbers of circulating naive T cells and cell-mediated immune responses which may play a role in the increased tumorigenesis, autoimmunity, and infectious diseases observed within an aging host. Despite the extensive study of the pathophysiology of the aging thymus, the precise molecular mechanism involved in the involution process remains unclear. In an effort to profile molecular changes that occur within the aging thymus, microarray analysis was performed using RNA derived from thymus isolated from mice of varying ages. Using mRNA derived from the progressively aging thymi and spleens, microarray analysis was performed using three distinct custom-made cDNA microarrays developed within our laboratory as well as 26K oligonucleotide murine arrays. The success of this project relies upon the reliability of the molecular profiling of aged cells from defined aged sources, both from culture and freshly isolated aged cells. The first milestone will be the definitive characterization and selection of genes associated with thymic involution. Subsequently, we plan to conduct serial analysis of gene expression (SAGE) in the thymi and spleens of mice of varying ages, H-2 and genetic backgrounds, and known involution mouse models. Our current data would suggest that thymic involution may be strain dependent and may in part be associated with distinct genetic factors rather than simply aging. We are currently analyzing the data obtained from the gene profiles of aged spleens, thymi, bone marrow, B cells, T cells and thymocytes from mice of various ages as well as from aged mice infused with GH, ghrelin or leptin. It is unclear whether certain lymphoid organs or cellular components play a critical role in longevity and life span. The overall goal of this project is to produce a comprehensive gene expression profile in the thymus, spleen, and lymph nodes during the aging process to identify unique and common genes and functionally related groups of genes that are expressed in an age-dependent manner in these different organ systems. |
| Role for Homocysteine in Immunoregulation and Disease Pathology: Homocysteine (Hcy) is the immediate precursor of the amino acid, methionine. In humans, blood concentrations of Hcy may become elevated as a result of deficiency in folate, vitamin B6 or vitamin B12 and has recently been identified as a putative risk factor for a number of age-associated disease states including arteriosclerosis, myocardial infarction, arterial occlusive disease, Alzheimer's disease and neural tube defects. A specific role for Hcy or any of its metabolites, such as S-adenosyl Hcy (SAH) or Hcy thiolactone, in these conditions has not yet been firmly established. Particularly absent is a description of the effects of elevated Hcy levels on immune function. Several studies have examined the effects of Hcy on monocyte, neutrophil and B cell function, inflammation and chemokine production; however, little is known about the Hcy effects on T lymphocytes. Our initial studies revealed that treatment of resting human T cells with Hcy resulted in a dose-dependent increase in apoptotic cell death. D,L Hcy was more potent than Hcy thiolactone in this respect while SAH was found to be significantly less active or inactive in many cases. We also found that the pro-apoptotic effects of Hcy were abrogated with the addition of pan-caspase PARP inhibitors to the cell cultures. These results suggest that D,L-Hcy, like other apoptotic stressors, leads to the activation of the caspase cascade and eventually to the cleavage of the key cellular proteins, like PARP, eventually leading to the typical morphological changes observed in cells undergoing apoptosis. We have also found that Hcy-mediated apoptosis is inhibited by the phosphatase and protein synthesis inhibitors, calcium chelators, Bcl-2, and Bcl-xl. Moreover, we have also found that Hcy appears to potentiate cellular death induced by a number of other established apoptotic signals including activation-induced cell death (AICD), heat shock, and Fas ligand- and HIV-mediated T cell death. In addition to the pro-apoptotic effects of Hcy, stimulation of mononuclear cells or isolated T cells with immobilized anti-CD3 mAb in the presence of Hcy or thiolactone but not SAH resulted in a significant increase in cell division and expression of several type 1 cytokines. More detailed examination of the Hcy effects on T cell activation revealed that this type 1 cytokine production profile is mediated, in part, through the production of IL-18 and possibly IL-12. The precise mechanism involved in the generation of these cytokines is currently under investigation but we believe the Hcy effect is being mediated, in part, by specific stress-associated signals resulting from Hcy treatment. Overall, Hcy appears to exert a number of differential effects on immune cells, which may alter immune function in the circulation and tissue microenvironment with age and disease pathology. A greater understanding of the potential modulatory effects of Hcy and its metabolites on immune function may result in the development of potential therapeutic strategies to control and optimize immune responses with age and in various age-associated disease states. |
| Contact Information: Laboratory of Immunology Biomedical Research Center, room 08C222 251 Bayview Boulevard, Suite 100 Baltimore, MD 21224-6825 Phone 410-558-8159 Fax 410-558-8284 E mail taubd@grc.nia.nih.gov For more information about the Laboratory: http://www.grc.nia.nih.gov/branches/li/li.htm |
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