Analysis of global gene expression in immune cells has provided unique insights into immune system function and response to infection. Recently, we applied microarray and serial analysis of gene expression (SAGE) techniques to the study of gammadelta T-cell function in humans and cattle. The intent of this review is to summarize the knowledge gained since our original comprehensive studies of bovine gammadelta T-cell subsets. More recently, we have characterized the effects of mucosal infection or treatment with microbial products or mitogens on gene expression patterns in sorted gammadelta and alphabeta T-cells. These studies provided new insights into the function of bovine gammadelta T-cells and led to a model in which response to pathogen-associated molecular patterns (PAMPs) induces 'priming' of gammadelta T-cells, resulting in more robust responses to downstream cytokine and/or antigen signals. PAMP primed gammadelta T-cells are defined by up-regulation of a select number of cytokines, including MIP1alpha and MIP1beta, and by antigens such as surface IL2 receptor alpha (IL-2Ralpha) and CD69, in the absence of a prototypic marker for an activated gammadelta T-cell, IFN-gamma. Furthermore, PAMP primed gammadelta T-cells are more capable of proliferation in response to IL-2 or IL-15 in the absence of antigen. PAMPs such as endotoxin, peptidoglycan and beta-glucan are effective gammadelta T-cell priming agents, but the most potent antigen-independent priming agonists defined to date are condensed oligomeric tannins produced by some plants.
Leukocyte adhesion and migration are mediated partially by CD11b/CD18 (membrane-activated complex-1, CR3). Earlier studies have demonstrated a role for green tea polyphenols in down-regulating CD11b on CD8(+) T cells and monocytes. We have shown recently a stimulatory effect of unripe apple polyphenols (APP) on gammadelta T cells. Thus, we compared the effect of APP on bovine gammadelta T cell and monocyte CD11b expression. Purified bovine monocytes and monocyte-depleted PBLs were cultured with APP. CD11b levels decreased on monocytes in response to APP. In contrast, a gammadelta T cell subset responded to APP by up-regulating CD11b. The CD11b regulation was not seen on gammadelta T cells or monocytes treated with APP fractions depleted of tannins. The APP-induced down-regulation of CD11b on monocytes was inhibited by an anti-CD11b mAb, consistent with previous studies showing that polyphenols bind CD11b. As expected, the anti-CD11b mAb had no effect on the APP response in resting gammadelta T cells, as these cells lacked CD11b. Consistent with the changes in surface CD11b expression, APP-treated gammadelta T cells showed increased adherence to plastic, whereas monocyte adhesion was reduced. APP also induced cytokine gene expression in gammadelta T cells. Some polyphenols are thought of as anti-inflammatory agents; however, these data, as well as other ongoing studies, indicate they have a proinflammatory effect on gammadelta T cells. In vivo, plant polyphenols may enhance gammadelta T cell migration and function at sites of inflammation, where they could induce rapid, immune-regulatory and innate-like immune responses.
Many pharmaceutical drugs arc isolated from plants used in traditional medicines, and new plant-derived pharmaceutical drugs continue to be identified. Relevant to this review, different plant-derived agonists for gammadelta T cells are described that impart effector functions upon distinct subsets of these cells. Recently, plant tannins have been defined as one class of gammadelta T cell agonist and appear to preferentially activate the mucosal population. Mucosal gammadelta T cells function to modulate tissue immune responses and induce epithelium repair. Select tannins, isolated from apple peel, rapidly induce immune gene transcription in gammadelta T cells, leading to cytokinc production and increased responsiveness to secondary signals. Activity of these tannin preparations tracks to the procyanidin fraction, with the procyanidin trimer (C1) having the most robust activity defined to date. The response to the procyanidins is evolutionarily conserved in that responses are seen with human, bovine, and murine gammadelta T cells, although human cells show less selectivity. Procyanidin-induced responses described in this review likely account for the expansion of mucosal gammadelta T cells seen in mice and rats fed soluble extracts of tannins. Use of procyanidins to activate gammadelta T cells may represent a novel approach for the treatment of tissue damage and autoimmune diseases.
Yamoa™ (ground bark of Funtumia elastica tree) is marketed and sold as a dietary supplement with anecdotal therapeutic effects in the treatment of asthma and hay fever. We determined that Yamoa™ and Yamoa™-derived polysaccharides affected innate immunity, in part, by priming γδ T cells. Gene expression patterns in purified bovine γδ T cells and monocytes induced by Yamoa™ were similar to those induced by ultrapure lipopolysaccharide (uLPS). In the presence of accessory cells, Yamoa™ had priming effects that were similar to those of LPS on bovine and murine γδ T cells, but much more potent than LPS on human γδ T cells. The bioactive component of Yamoa™ was delineated to a complex polysaccharide fraction (Yam-I). Intraperitoneal injection of Yamoa™ and Yam-I in mice induced rapid increases in peritoneal neutrophils directed by changes in chemokine expression. In support of a unique agonist found in Yam-I, similar peritonitis responses were also observed in TLR4-and MyD88-deficient mice. Therapeutic treatment with Yam-I resulted in decreased bacterial counts in feces from mice with Salmonella enterica serotype Typhimurium (ST)-induced enterocolitis. This characterization of the immune stimulatory properties of polysaccharides derived from Yamoa™ suggests mechanisms for the anecdotal positive effects of its ingestion and that these polysaccharides show potential for application in innate protection from disease.
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