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Recent Advances in Nutritional Sciences

Bioactive Food Components that Enhance T Cell Function May Play a Role in Cancer Prevention¹

² Food Science and Human Nutrition, University of Florida, Gainesville, FL 32611; ³ Divison of Rheumatology, Allergy, and Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; ⁴ Nutritional Science Research Institute, Boston, MA 02115; and ⁵ Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, NIH, Rockville, MD 20892

^* To whom correspondence should be addressed. E-mail: percival{at}ufl.edu.

	ABSTRACT

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T cells are found largely within the epithelium and recognize antigens differently than their β T cell counterparts. TCR ^–/– 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 T cell cytotoxicity, cytokine secretion, and proliferative capacity, and the results are nonetheless intriguing. Among other functions, T cells play a role in immunosurveillance against malignant cells, as shown by the T cell receptor (TCR)^–/– knock out mice that exhibit a rapid tumor onset and increased tumor incidence. Some common dietary modifiers of 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 T cells. Clinical studies also document that the oral consumption of a tea component, L-theanine, enhances T cell proliferation and interferon- 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 TCR^–/– 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 T interrelationship may not be simple, the societal implications are enormous.

	Introduction

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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 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 T cell interrelationship are highlighted.

In human blood, the largest subset of T cells expresses a unique, highly conserved surface T cell receptor (TCR), resulting in a distinct antigen specificity, which sets them apart from their β T cell counterparts (3). Unlike β T cells, 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 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 T cells.

Mounting evidence suggests that 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 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 T cells.

Another candidate trigger for increased 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 assciated with the risk of cancer and other disease (15). HSP72 significantly induced proliferation of T cells, whereas 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 T cells may occur either through direct or indirect processes.

Can 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 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 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 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 T cells

Changes in allergic reactions may also provide indirect evidence that diet influences T cells. Children with an untreated food allergy had a significantly higher density of 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 β cells were not altered. In 2 strains of mice, oral sensitization with ovalbumin did not alter 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 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 T cell density, leading them to conclude that polymerization of the tannins was an important part of the immune modulation. Overall, they concluded that the 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 T cells (30). The addition of 0.4% nucleotides to the diets of weanling mice for 2 wk increased that T cell proportion from 50.6 to 58.7%. In addition, these cells secreted more IL-7, but not IL-2 or interferon- (IFN).

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 T cells. 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 of 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 T cells increased first, followed by the β T cells, and then NK cells (56 to 72 d). T cells almost doubled due to dietary treatment with CLA. It should be noted that vaccination also causes a 2.5-fold increase in T cell numbers. Vaccination, in addition to CLA, increased 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 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 -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 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 IFN 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 of T cells, it boosted, ex vivo, by 2- to 3-fold, the capacity of T cells to secrete IFN 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 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 T 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 T cells. About a 30% increase in circulating 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 T cells to secrete IFN, 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 IFN mRNA 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 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 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 T cell function.

	FOOTNOTES

 
¹ Author disclosures: J. F. Bukowski, NSRI director and consultant for Taiyo, Inc.; S. S. Percival and J. Milner, no conflicts of interest.

⁶ Abbreviations used: ACT, apple condensed tannins; CLA, conjugated linoleic acid; EGCG, epigallocatechin gallate, HSP, heat shock protein; IFN, interferon; IL, interleukin; PBMC, peripheral blood mononuclear cells; TCR, T cell receptor.

Manuscript received 12 September 2007.

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