γδ T cells are a functionally heterogeneous population and contribute to many early immune responses. The majority of their activity is described in humans and mice, but the immune systems of all jawed vertebrates include the γδ T cell lineage. Although some aspects of γδ T cells vary between species, critical roles in early immune responses are often conserved. Common features of γδ T cells include innate receptor expression, antigen presentation, cytotoxicity, and cytokine production. Herein we compare studies describing these conserved γδ T cell functions and other, potentially unique, functions. γδ T cells are well documented for their potential immunotherapeutic properties; however, these proposed therapies are often focused on human diseases and the mouse models thereof. This review consolidates some of these studies with those in other animals to provide a consensus for the current understanding of γδ T cell function across species.

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 γδ 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 γδ 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 γδ and αβ T-cells. These studies provided new insights into the function of bovine γδ T-cells and led to a model in which response to pathogen-associated molecular patterns (PAMPs) induces ‘priming’ of γδ T-cells, resulting in more robust responses to downstream cytokine and/or antigen signals. PAMP primed γδ T-cells are defined by up-regulation of a select number of cytokines, including MIP1α and MIP1β, and by antigens such as surface IL2 receptor α (IL-2Rα) and CD69, in the absence of a prototypic marker for an activated γδ T-cell, IFN-γ. Furthermore, PAMP primed γδ 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 β-glucan are effective γδ T-cell priming agents, but the most potent antigen-independent priming agonists defined to date are condensed oligomeric tannins produced by some plants.

The Açaí (Acai) fruit is a popular nutritional supplement that purportedly enhances immune system function. These anecdotal claims are supported by limited studies describing immune responses to the Acai polyphenol fraction. Previously, we characterized γδ T cell responses to both polyphenol and polysaccharide fractions from several plant-derived nutritional supplements. Similar polyphenol and polysaccharide fractions are found in Acai fruit. Thus, we hypothesized that one or both of these fractions could activate γδ T cells. Contrary to previous reports, we did not identify agonist activity in the polyphenol fraction; however, the Acai polysaccharide fraction induced robust γδ T cell stimulatory activity in human, mouse, and bovine PBMC cultures. To characterize the immune response to Acai polysaccharides, we fractionated the crude polysaccharide preparation and tested these fractions for activity in human PBMC cultures. The largest Acai polysaccharides were the most active in vitro as indicated by activation of myeloid and γδ T cells. When delivered in vivo, Acai polysaccharide induced myeloid cell recruitment and IL-12 production. These results define innate immune responses induced by the polysaccharide component of Acai and have implications for the treatment of asthma and infectious disease.

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 γδ T cells are described that impart effector functions upon distinct subsets of these cells. Recently, plant tannins have been defined as one class of γδ T cell agonist and appear to preferentially activate the mucosal population. Mucosal γδ T cells function to modulate tissue immune responses and induce epithelium repair. Select tannins, isolated from apple peel, rapidly induce immune gene transcription in γδ 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 γδ T cells, although human cells show less selectivity. Procyanidin-induced responses described in this review likely account for the expansion of mucosal γδ T cells seen in mice and rats fed soluble extracts of tannins. Use of procyanidins to activate γδ T cells may represent a novel approach for the treatment of tissue damage and autoimmune diseases.

Pulmonary Francisella tularensis and Burkholderia pseudomallei infections are highly lethal in untreated patients, and current antibiotic regimens are not always effective. Activating the innate immune system provides an alternative means of treating infection and can also complement antibiotic therapies. Several natural agonists were screened for their ability to enhance host resistance to infection, and polysaccharides derived from the Acai berry (Acai PS) were found to have potent abilities as an immunotherapeutic to treat F. tularensis and B. pseudomallei infections. In vitro, Acai PS impaired replication of Francisella in primary human macrophages co-cultured with autologous NK cells via augmentation of NK cell IFN-γ. Furthermore, Acai PS administered nasally before or after infection protected mice against type A F. tularensis aerosol challenge with survival rates up to 80%, and protection was still observed, albeit reduced, when mice were treated two days post-infection. Nasal Acai PS administration augmented intracellular expression of IFN-γ by NK cells in the lungs of F. tularensis-infected mice, and neutralization of IFN-γ ablated the protective effect of Acai PS. Likewise, nasal Acai PS treatment conferred protection against pulmonary infection with B. pseudomallei strain 1026b. Acai PS dramatically reduced the replication of B. pseudomallei in the lung and blocked bacterial dissemination to the spleen and liver. Nasal administration of Acai PS enhanced IFN-γ responses by NK and γδ T cells in the lungs, while neutralization of IFN-γ totally abrogated the protective effect of Acai PS against pulmonary B. pseudomallei infection. Collectively, these results demonstrate Acai PS is a potent innate immune agonist that can resolve F. tularensis and B. pseudomallei infections, suggesting this innate immune agonist has broad-spectrum activity against virulent intracellular pathogens. Activation of the innate immune system offers an alternative and effective means to counter infection, particularly, in cases when the etiologic agent is unknown, such as a potential bioterrorism attack or when the agent is resistant to antibiotics. Here we report that a natural polysaccharide extract derived from the Acai berry (Acai PS) has potent abilities to counter infection when applied as a mucosal immunotherapeutic. Acai PS diminishes the replication of F. tularensis in human macrophages co-cultured with NK cells in vitro. In addition, nasal treatment of mice, prophylactically or therapeutically, with Acai PS results in significant protection against morbidity and mortality against pulmonary infection with virulent F. tularensis or B. pseudomallei. Of particular interest is that Acai PS utilizes the same mechanism of protection by enhancing Th1 cell immunity by both human and murine cells. Since an optimal Th1-type response is required for protection against a wide variety of infectious diseases, Acai PS represents a novel immunotherapeutic that could augment antibiotic therapy against a broad range of pathogens.