~Sending a flashback to plenty of love: (As seen on Twitter, Re-made T-Cells Vanquish Cancer and from further reading STI,A.I.Ds,viruses etc. (I suggest a full read through this note):*soursop apparently also does wonders*: ~Sending a flashback to plenty of love: T-Cell Cures to almost Everything - What to ask after a diagnosis; The following information has been provided/collective through, The Journal of Nutrition: jn.nutrition.org/content/138/1/1.long © 2008 American Society for Nutrition Bioactive Food Components that Enhanceγδ T Cell Function May Play a Role in Cancer Prevention1 Susan S. Percival2,*, Jack F. Bukowski3,4, and John Milner5 +Author Affiliations 2Food Science and Human Nutrition, University of Florida, Gainesville, FL 32611; 3Divison of Rheumatology, Allergy, and Immunology, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA 02115; 4Nutritional Science Research Institute, Boston, MA 02115; and 5Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, NIH, Rockville, MD 20892 ↵*To whom correspondence should be addressed. E-mail: [email protected]. Next Section Abstract γδ T cells are found largely within the epithelium and recognize antigens differently than their αβ T cell counterparts. TCR δ−/− knock out mice exhibit a rapid tumor onset, along with increased tumor incidence. Although limited, research demonstrates that nutrients and bioactive food components can influence γδ T cell cytotoxicity, cytokine secretion, and proliferative capacity, and the results are nonetheless intriguing. Among other functions, γδ T cells play a role in immunosurveillance against malignant cells, as shown by the T cell receptor (TCR)δ−/− knock out mice that exhibit a rapid tumor onset and increased tumor incidence. Some common dietary modifiers of γδ T cell numbers or activity are apple condensed tannins, dietary nucleotides, fatty acids, and dietary alkylamines. A recent clinical study demonstrated that ingesting a fruit and vegetable juice concentrate increased the number of circulating γδ T cells. Clinical studies also document that the oral consumption of a tea component, L-theanine, enhances γδ T cell proliferation and interferon-γ secretion. The significance of these studies awaits additional examination of the influence of exposures and duration on these and other food components. Adoptive transfer and TCRδ−/− knock out mice models should be used more extensively to determine the physiological impact of the number and activity of these cells as a function of dietary component exposures. While clarifying the diet and γδ T interrelationship may not be simple, the societal implications are enormous. Previous SectionNext Section Introduction About one-third of all cancers in the Western world are thought to be diet related (1) and thus are potentially preventable or modifiable by appropriate dietary interventions. The caveat that is not always mentioned from Doll and Peto (1) states: “although this figure of 35 percent is a plausible total, the parts that contribute to it are uncertain in the extreme, so the degree of uncertainty of the total should be obvious, and we make no pretense of its reliability.” Nonetheless, these findings serve as the basis for the theory that diet contributes to the incidence of cancer by either over-consumption of certain food items or not enough of others. Dietary components may modify the risk of cancer by influencing multiple processes, including DNA repair, cell proliferation, differentiation, apoptosis, angiogenesis, etc. A shift in immunocompetence and immunosurveillance may also explain part of the diet-cancer interrelationship. Suppression of immunity is associated with an increased risk of malignancy (2). Thus, it is reasonable to speculate that maintenance or strengthening of immunity will lead to a reduction in cancer risk. Evidence presented in this review, albeit limited, points to diet as a modifier of tumoricidal activity by a specific cell. We summarize strengths and weaknesses of the evidence indicating that diet-mediated changes in γδ T cell activity lead to a subsequent change in immunosurveillance. Likewise, research opportunities that are needed to define the physiological significance of the diet and γδ T cell interrelationship are highlighted. In human blood, the largest subset of γδ T cells expresses a unique, highly conserved surface T cell receptor (TCR), resulting in a distinct antigen specificity, which sets them apart from their αβ T cell counterparts (3). Unlike αβ T cells, γδ T cells do not generally recognize peptide antigens processed and displayed on antigen-presenting cell surfaces (4). Nonpeptide prenyl pyrophosphates (5–7), phosphorylated uridine and thymidine compounds (8), bisphosphonates (6,9,10), and alkylamines (11,12), have all been shown to activate or prime γδ T cells. Alkylamines can be acquired from the diet and include compounds such as ethylamine, propylamine, butylamine, and amylamine. The literature discussed here describes several other dietary compounds that influence γδ T cells. Mounting evidence suggests that γδ cells do not only recognize foreign, nonpeptide antigens, but also respond to signals of self-distress, Support for this response comes from studies that show that human γδ T cells recognize metabolites of the mevalonate pathway (13). The mevalonate pathway is common to all cells and is sometimes upregulated in tumor cells (14). A variety of food components, including cholesterol, isoprenoids, genistein, (n-3) fatty acids, etc., are known to influence the mevalonate pathway (14); thus it is difficult to uncouple what direct and indirect role that diet may have on γδ T cells. Another candidate trigger for increased γδ T cells may arise from increases in 1 or more of the heat shock proteins (HSP).6 Upregulation of HSP within host macrophages is associated with cytokine secretion, crosstalk between immune cells, and protection against infection, while upregulation of HSP from bacteria has been associated with the risk of cancer and other disease (15). HSP72 significantly induced proliferation of γδ T cells, whereas γδ T cells showed a pronounced cytotoxicity to transformed cells that was reduced in HSP knock out mice (16). Dietary factors as diverse as nickel (17), carnitine (18,19), and energy restriction (20,21) have been reported to influence HSP. Thus, again, the influence of diet on γδ T cells may occur either through direct or indirect processes. Can γδ T cell activity be enhanced by diet or bioactive food components? Very little data exist to answer this question, but there is enough intriguing information to justify further research. An increase in γδ T cell activity has been defined broadly to include an increase in cell number and an increased ability to proliferate, secrete cytokines, kill tumor or infected cells, or to express adhesion or cytotoxic molecules on the cell surface. Modifications in cytokine or chemokine transcription, translation, synthesis, or secretion may also be interpreted as beneficial antitumor activity of γδ T cells. The process of surveillance involves genes, RNA, proteins, cell adhesion molecules, cytokines, interactions with other cells and lymphoid tissue, antigen recognition, cellular differentiation, migration and localization to tissues, the activation state, and cytotoxicity. Modification of any of these functions of γδ T cells by nutrients or bioactive food components has the potential to be related to cancer prevention (Table 1). View this table: In this window In a new window TABLE 1 Bioactive food compounds that have been shown to alter γδ T cells Since the mid-1990s, a fermented mistletoe extract has been used in a host of clinical studies in cancer patients in Germany and Switzerland (22–24). The studies reveal an improvement in survival, a better quality of life, and reduced metastases in those taking the extract. One study showed an increase in interleukin (IL)-12 levels (25), a cytokine known to support the proliferation and cytotoxicity of γδ T cells (26). Fischer et al. (27) showed that mistletoe extracts (50–500 mg/L) increased proliferation of γδ T cells in vitro by flow cytometry and tritiated thymidine incorporation in a dose dependent manner. Changes in allergic reactions may also provide indirect evidence that diet influences γδ T cells. Children with an untreated food allergy had a significantly higher density of γδ T cell in duodenal specimens than children with a treated food allergy (elimination diet) or in the control children (28). It should be noted that total CD3+ cells and αβ cells were not altered. In 2 strains of mice, oral sensitization with ovalbumin did not alter γδ cell numbers in the intestinal epithelium (29). Feeding apple condensed tannins (ACT) and then challenging the mice with ovalbumin resulted in much less severe anaphylaxis, demonstrated by a 50% lower histamine levels, 75% less serum immunoglobulin E, and a mean 0.4°C drop in body temperature, compared with the controls that dropped a mean of 1.5°C. This effect was dose dependent, with the least severe anaphylaxis in mice consuming 1% in their drinking water compared with 0.1 and 0.5%. When the lymphocyte populations in the intestinal epithelium were examined, the γδ T cells were significantly increased in the mice consuming ACT, regardless of whether they were sensitized or not. These investigators also provided a mixture of (+)-catechin and (−)-epicatechin to the animals, however, this did not change the γδT cell density, leading them to conclude that polymerization of the tannins was an important part of the immune modulation. Overall, they concluded that the γδ T cell plays a protective role in food allergies and that polymerized condensed tannins can stimulate this particular cell type in the intestinal mucosa and prevent detrimental effects from a challenge. Dietary nucleotides have been shown to impact the percentage of intestinal intraepithelial γδ T cells (30). The addition of 0.4% nucleotides to the diets of weanling mice for 2 wk increased that γδ T cell proportion from 50.6 to 58.7%. In addition, these cells secreted more IL-7, but not IL-2 or interferon-γ (IFNγ). Dietary fatty acids are known to alter composition of membranes and, in doing so, alter cell function, including the function of immune cells. Mice were fed a diet rich in olive oil [18:1 (n-9)], safflower oil [18:2 (n-6)], linseed oil [18:3 (n-3)], or fish oil [20:5 (n-3) and 22:6 (n-3)] for 5 mo through 2 gestational periods (31). Offspring from the second breeding cycle were fed the same diet as their dam for 42 d and killed. Several immune indices were different among the diets, including splenic γδ T cells. γδ T cells were statistically higher in the safflower diet than in the fish oil diet. The response to the variation in the (n-6):(n-3) ratio suggested possible involvement of eicosanoids, however, this was not specifically examined. Conjugated linoleic acid (CLA) has also been reported to influence the number ofγδ T cells. In pigs fed 1.33 g CLA/100 g diet [18:2(n-6)] for 72 d (32), marked changes were detected after 49 d. The number of γδ T cells increased first, followed by the αβ T cells, and then NK cells (56 to 72 d). γδ T cells almost doubled due to dietary treatment with CLA. It should be noted that vaccination also causes a 2.5-fold increase in γδ T cell numbers. Vaccination, in addition to CLA, increased γδ T cell numbers to the greatest extent (6-fold), more than dietary CLA alone (3.5-fold) or no dietary intervention (32). Alkylamine compounds have been shown to prime γδ T cells (9,11). These compounds, such as ethylamine, butylamine, and propylamine, are secreted by commensal gut bacteria as well as by pathogenic bacteria. These antigens are also found at mmol/L concentrations in various human body secretions, including breast milk, amniotic fluid, vaginal secretions, and urine. Additionally, they can be derived from foods and beverages such as kola nuts (33), tea, apple skins, red and white wine, mushrooms (Badius sp), and certain edible cucumbers (9). Green tea consumption is associated with a reduced risk for cancers of the breast, colorectum, lung, prostate, ovaries, and pancreas, (34,35). Many of these observations are thought to be due to epigallocatechin-3 gallate (EGCG) and other polyphenols found in tea (36–38). However, L-theanine, an amino acid representing about half of the 3–4% amino acids in tea leaves, may also be a contributing factor. Also known as γ-glutamylethylamine, L-theanine is metabolized in the kidney, to glutamic acid and ethylamine, with peak blood levels of L-theanine and ethylamine occurring 0.5 and 2 h after administration, respectively (39–41). Drinking tea increases urinary ethylamine (42). Ethylamine has been shown to cause a 15-fold expansion of γδ T cells when mixed with peripheral blood mononuclear cells (PBMC) isolated from healthy human subjects (9). PBMC incubated with ethylamine or iso-butylamine were challenged with bacteria. Cells incubated with either alkylamine were shown to be primed for expansion when challenged with bacterial antigen or lipopolysaccharide, as noted by an increase in IFNγ secretion (9,11). The effects of dietary alkylamines have also been examined in humans drinking black tea (600 mL/d containing 2.2 mmol/L L-theanine) or coffee (caffeine, but no L-theanine). Although tea drinking had no effect on the absolute numbers ofγδ T cells, it boosted, ex vivo, by 2- to 3-fold, the capacity of γδ T cells to secrete IFNγ in response to bacterial pathogens or nonpeptide antigens, compared with baseline controls (11). These results demonstrate that consumption of a food can influence the activity of γδ T cells in a favorable direction. Overall, this change is consistent with an improvement in immunosurveillance and, as a result, perhaps destruction of transformed cells. Studies that characterize the quantity and duration of human exposure to bioactive food components are now needed to fully understand this particular γδT cell response. A double-blind placebo-controlled clinical study in healthy subjects, mean age 26 y old, consuming capsules of juiced and dried fruit and vegetable mixture (NSA) for 11 wk was recently conducted and found to influence γδ T cells. About a 30% increase in circulating γδ T cells occurred in individuals taking the active capsules compared with the placebo group (P = 0.049). The individuals taking the treatment also had fewer symptoms of colds and flu during the study period (43). In a double-blind placebo-controlled trial of healthy human subjects 18–70 y old, a proprietary mixture of green tea components standardized for L-theanine and EGCG content (NSRI), taken orally over 3 mo, decreased the incidence of cold and flu symptoms by 30%. This protection correlated with a 30% increase, compared with placebo, in the ability of γδ T cells to secrete IFNγ, and to proliferate ex vivo in response to challenge with ethylamine (44). Microarray analysis of ex vivo ethylamine-stimulated cells confirmed that ingesting this mixture increased IFNγmRNA by 30%, compared with placebo, whereas IL-8 mRNA levels were not affected. In the same trial, the green tea formula decreased serum amyloid alpha, a marker of chronic inflammation, by 42%, and peroxidized serum lipids by 13% (S. S. Percival, J. F. Bukowski, J. Milner, and M. P. Nantz, unpublished data). Thus, this standardized formulation of L-theanine and EGCG combines to yield a result that enhances innate immunity while at the same time inhibiting harmful inflammation. Although tumoricidal activity was not directly studied in either the fruit and vegetable or L-theanine studies, the data suggest that through greater numbers and increased cytokine secretion, the γδ T cells would also be active against tumor cells. Additional studies are needed to verify this response and its overall physiological implications. The enhancement of immune function may not always provide improved health. It is conceivable that, although cancer risk may be reduced, the risk of other diseases may be increased. For example, there is evidence to suggest that over-activated γδ T cells may enhance the pathology associated with inflammatory bowel (45) or celiac disease (46). Additional research is needed to determine the appropriate exposures of bioactive food components necessary to bring about a beneficial response, and to determine whether there are vulnerable populations who will be placed at risk by such a dietary change. There is no doubt that proper nutrition has a role in overall immune function. Although animal and cell culture models provide tantalizing evidence that nutrients and other bioactive food components can influence tumoricidal cell activities, it is less apparent if these changes lead to enhanced cancer prevention in vivo. Although it is logical that a change in tumoricidal cell activity will coincide with cancer prevention, direct evidence for this is lacking, and thus firm conclusions regarding physiological importance currently cannot be made. Additional studies are needed to test the physiological relevance of bioactive food components as regulators of γδ T cell function.
Posted on: Fri, 03 Oct 2014 01:35:37 +0000
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