γδ T cells are innate immune cells that participate in host responses against many pathogens and cancers. Recently, phosphoantigen-based drugs, capable of expanding γδ T cells in vivo, entered clinical trials with the goal of enhancing innate immune system functions. Potential shortcomings of these drugs include the induction of nonresponsiveness upon repeated use and the expansion of only the Vδ2 subset of human γδ T cells. Vδ1 T cells, the major tissue subset, are unaffected by phosphoantigen agonists. Using FACS-based assays, we screened primary bovine cells for novel γδ T cell agonists with activities not encompassed by the current treatments in an effort to realize the full therapeutic potential of γδ T cells. We identified γδ T cell agonists derived from the condensed tannin fractions of Uncaria tomentosa (Cat’s Claw) and Malus domestica (apple). Based on superior potency, the apple extract was selected for detailed analyses on human cells. The apple extract was a potent agonist for both human Vδ1 and Vδ2 T cells and NK cells. Additionally, the extract greatly enhanced phosphoantigen-induced γδ T cell expansion. Our analyses suggest that a tannin-based drug may complement the phosphoantigen-based drugs, thereby enhancing the therapeutic potential of γδ T cells.

Following a ligand-based drug design approach, a potent mixed formyl peptide receptor 1 (FPR1) and formyl peptide receptor-like 1 (FPRL1) agonist (14a) and a potent and specific FPRL1 agonist (14x) were identified. These compounds belong to a large series of pyridazin-3(2H)-one derivatives substituted with a methyl group at position 6 and a methoxy benzyl at position 4. At position 2, an acetamide side chain is essential for activity. Likewise, the presence of lipophilic and/or electronegative substituents in the position para to the aryl group at the end of the chain plays a critical role for activity. Affinity for FPR1 receptors was evaluated by measuring intracellular calcium flux in HL-60 cells transfected with FPR1, FPRL1, and FPRL2. Agonists were able to activate intracellular calcium mobilization and chemotaxis in human neutrophils. The most potent chemotactic agent (EC50 = 0.6 μM) was the mixed FPR/FPRL1 agonist 14h.

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.

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.

Autoreactive B lymphocytes that are not culled by central tolerance in the bone marrow frequently enter the peripheral repertoire in a state of functional impairment, termed anergy. These cells are recognized as a liability for autoimmunity, but their contribution to disease is not well-understood. Insulin-specific 125Tg B cells support T cell-mediated Type 1 diabetes (T1D) in nonobese diabetic (NOD) mice, despite being anergic to B cell mitogens and T cell dependent immunization. Using this model, the potential of anergic, autoreactive B cells to present antigen and activate T cells was investigated. The data show that: a) insulin is captured and rapidly internalized by 125Tg BCRs, b) these antigen-exposed B cells are competent to activate both experienced and naïve CD4+ T cells, c) anergic 125Tg B cells are more efficient than naïve B cells at activating T cells when antigen is limiting, and d) 125Tg B cells are competent to generate low-affinity insulin B chain epitopes necessary for activation of diabetogenic anti-insulin BDC12-4.1 T cells, indicating the pathological relevance of anergic B cells in T1D. Thus, phenotypically tolerant B cells that are retained in the repertoire may promote autoimmunity by driving activation and expansion of autoaggressive T cells via antigen-presentation.