Structure–function relationships of immunostimulatory polysaccharides: A review

A comprehensive understanding of host-pathogen interactions requires a knowledge of the associated gene expression changes in both the pathogen and the host. Traditional, probe-dependent approaches using microarrays or reverse transcription PCR typically require the pathogen and host cells to be physically separated before gene expression analysis. However, the development of the probe-independent RNA sequencing (RNA-seq) approach has begun to revolutionize transcriptomics. Here, we assess the feasibility of taking transcriptomics one step further by performing 'dual RNA-seq', in which gene expression changes in both the pathogen and the host are analysed simultaneously.

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Dual RNA-seq of pathogen and host

With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.

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New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics.

Expression and function of Toll-like receptors in T lymphocytes

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future.

γδ T cells recognize unprocessed or non-peptide Ags, respond rapidly to infection, and localize to mucosal surfaces. We have hypothesized that the innate functions of γδ T cells may be more similar to those of cells of the myeloid lineage than to other T cells. To begin to test this assumption, we have analyzed the direct response of cultured human and peripheral blood bovine γδ T cells to pathogen associated molecular patterns (PAMPs) in the absence of APCs using microarray, real-time RT-PCR, proteome array, and chemotaxis assays. Our results indicate that purified γδ T cells respond directly to PAMPs by increasing expression of chemokine and activation-related genes. The response was distinct from that to known γδ T cell Ags and different from the response of myeloid cells to PAMPs. In addition, we have analyzed the expression of a variety of PAMP receptors in γδ T cells. Freshly purified bovine γδ T cells responded more robustly to PAMPs than did cultured human cells and expressed measurable mRNA encoding a variety of PAMP receptors. Our results suggest that rapid response to PAMPs through the expression of PAMP receptors may be another innate role of γδ T cells.

γδ T Cells Respond Directly to Pathogen-Associated Molecular Patterns

To elucidate the functions of circulating gammadelta T cells, in the absence of antigen stimulation, the differential gene expression of two circulating gammadelta T cell subsets was analyzed. The two subsets, with distinct trafficking phenotypes in young calves, were GD3.5(+), CD8(-), WC1(+) or GD3.5(-), CD2(+), WC1(-), and 90-100% CD8(+) and were sorted based on GD3.5 and gammadelta T cell receptor expression. Results from two different human arrays probed with cDNA from these gammadelta T cell subsets indicated that they have markedly different tissue-specific functions. The genes preferentially expressed by GD3.5(+) (CD8(-)) gammadelta T cells demonstrated that they were highly activated, proliferative, and inflammatory, whereas those expressed by GD3.5(-) (primarily CD8(+)) gammadelta T cells were involved in promoting quiescence, consistent with a role for gammadelta T cells as sentinel mucosal cells, and several were interferon-regulated genes. Gene expression and phenotypic assays indicated that CD8(+) gammadelta T cells were apoptotic, whereas CD8(-) gammadelta T cells were apoptosis-resistant. Differential expression of multiple genes was confirmed in both arrays: That of 14 genes was confirmed by quantitative reverse transcriptase-polymerase chain reaction and that of seven proteins was confirmed by flow cytometry. This novel, genomic analysis of circulating gammadelta T cell subsets, without confounding effects of the tissue microenvironment, offers new insight into the biology and development of neonatal gammadelta T cells.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0902453

Differential mRNA expression in circulating γδ T lymphocyte subsets defines unique tissue-specific functions

Gene expression profiles were compared in circulating bovine GD3.5+ (CD8-) and GD3.5- (predominantly CD8+) gammadelta T cells using serial analysis of gene expression (SAGE). Approximately 20,000 SAGE tags were generated from each library. A comparison of the two libraries demonstrated 297 and 173 tags representing genes with 5-fold differential expression in GD3.5+ and GD3.5- gammadelta T cells, respectively. Consistent with their localization into sites of inflammation, GD3.5+ gammadelta T cells appeared transcriptionally and translationally more active than GD3.5- gammadelta cells. GD3.5- gammadelta T cells demonstrated higher expression of the cell proliferation inhibitor BAP 37, which was associated with their less activated gene expression phenotype. The immune regulatory and apoptosis-inducing molecule, galectin-1, was identified as a highly abundant molecule and was higher in GD3.5+gammadelta T cells. Surface molecules attributed to myeloid cells, such as CD14, CD68, and scavenger receptor-1, were identified in both populations. Furthermore, expression of B lymphocyte-induced maturation protein, a master regulator of B cell and myeloid cell differentiation, was identified by SAGE analysis and was confirmed at the RNA level to be selectively expressed in gammadelta T cells vs alphabeta T cells. These results provide new insights into the inherent differences between circulating gammadelta T cell subsets.

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Serial analysis of gene expression in circulating γδ T cell subsets defines distinct immunoregulatory phenotypes and unexpected gene expression profiles

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.

Comparative Biology of γδ T Cell Function in Humans, Mice, and Domestic Animals

The Acai (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

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Jodi F. Hedges

Papers

γδ T Cells Respond Directly to Pathogen-Associated Molecular Patterns

Differential mRNA expression in circulating γδ T lymphocyte subsets defines unique tissue-specific functions

Serial analysis of gene expression in circulating γδ T cell subsets defines distinct immunoregulatory phenotypes and unexpected gene expression profiles

Comparative Biology of γδ T Cell Function in Humans, Mice, and Domestic Animals

Polysaccharides isolated from Açaí fruit induce innate immune responses.