Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells

γδ T cells are a distinct subgroup of T cells containing T cell receptors (TCRs) γ and TCR δ chains with diverse structural and functional heterogeneity. As a bridge between the innate and adaptive immune systems, γδ T cells participate in various immune responses during cancer progression. Because of their direct/indirect antitumor cytotoxicity and strong cytokine production ability, the use of γδ T cells in cancer immunotherapy has received a lot of attention over the past decade. Despite the promising potential of γδ T cells, the efficacy of γδ T cell immunotherapy is limited, with an average response ratio of only 21%. In addition, research over the past 2 years has shown that γδ T cells could also promote cancer progression by inhibiting antitumor responses, and enhancing cancer angiogenesis. As a result, γδ T cells have a dual effect and can therefore be considered as being both “friends” and “foes” of cancer. In order to solve the sub-optimal efficiency problem of γδ T cell immunotherapy, we review recent observations regarding the antitumor and protumor activities of major structural and functional subsets of human γδ T cells, describing how these subsets are activated and polarized, and how these events relate to subsequent effects in cancer immunity. A mixture of both antitumor or protumor γδ T cells used in adoptive immunotherapy, coupled with the fact that γδ T cells can be polarized from antitumor cells to protumor cells appear to be the likely reasons for the mild efficacy seen with γδ T cells. The future holds the promise of depleting the specific protumor γδ T cell subgroup before therapy, choosing multi-immunocyte adoptive therapy, modifying the cytokine balance in the cancer microenvironment, and using a combination of γδ T cells adoptive immunotherapy with immune checkpoint inhibitors.

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Gamma-delta (γδ) T cells: friend or foe in cancer development?

Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs

Periodontitis is a common intraoral infection and is inextricably linked to systemic diseases. Recently, the regulation between host immunologic response and periodontal pathogens has become a hotspot to explain the mechanism of periodontitis and related systemic diseases. Since Porphyromonas gingivalis (P. gingivalis) was proved as critical periodontal pathogen above all, researches focusing on the mechanism of its virulence factors have received extensive attention. Studies have shown that in the development of periodontitis, in addition to the direct release of virulent factors by periodontal pathogens to destroy periodontal tissues, over-low or over-high intrinsic immune and inflammatory response mediated by Toll-like receptors (TLRs) can lead to more lasting destruction of periodontal tissues. It is very necessary to sort out how various cytopathic factors of P. gingivalis mediate inflammation and immune responses between the host through TLRs so as to help precisely prevent, diagnose, and treat periodontitis in clinic. This review summarizes the role of three most widely studied pathogenic factors produced by P. gingivalis (lipopolysaccharide, gingipains, pili) and their interactions with TLRs at the cellular and molecular level in the progress of periodontitis.

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Pathogenesis of Important Virulence Factors of Porphyromonas gingivalis via Toll-Like Receptors

How defined microbes influence the skin immune system remains poorly understood. Here we demonstrate that Corynebacteria, dominant members of the skin microbiota, promote a dramatic increase in the number and activation of a defined subset of γδ T cells. This effect is long-lasting, occurs independently of other microbes, and is, in part, mediated by interleukin (IL)-23. Under steady-state conditions, the impact of Corynebacterium is discrete and noninflammatory. However, when applied to the skin of a host fed a high-fat diet, Corynebacterium accolens alone promotes inflammation in an IL-23-dependent manner. Such effect is highly conserved among species of Corynebacterium and dependent on the expression of a dominant component of the cell envelope, mycolic acid. Our data uncover a mode of communication between the immune system and a dominant genus of the skin microbiota and reveal that the functional impact of canonical skin microbial determinants is contextually controlled by the inflammatory and metabolic state of the host.

https://rupress.org/jem/article-pdf/215/3/785/1169073/jem_20171079.pdf

Contextual control of skin immunity and inflammation by Corynebacterium.

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

Epilobium angustifolium is a medicinal plant used around the world in traditional medicine for the treatment of many disorders and ailments. Experimental studies have demonstrated that Epilobium extracts possess a broad range of pharmacological and therapeutic effects, including antioxidant, anti-proliferative, anti-inflammatory, antibacterial, and anti-aging properties. Flavonoids and ellagitannins, such as oenothein B, are among the compounds considered to be the primary biologically active components in Epilobium extracts. In this review, we focus on the biological properties and the potential clinical usefulness of oenothein B, flavonoids, and other polyphenols derived from E. angustifolium. Understanding the biochemical properties and therapeutic effects of polyphenols present in E. angustifolium extracts will benefit further development of therapeutic treatments from this plant. Copyright © 2016 John Wiley & Sons, Ltd.

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Therapeutic Potential of Polyphenols from Epilobium Angustifolium (Fireweed).

Oenothein B is a polyphenol isolated from Epilobium angustifolium and other plant sources, which has been reported to exhibit immunomodulatory properties. Oenothein B is known to activate myeloid cells and induce the production of IL-1 and other cytokines. However, its effects on lymphocytes are unknown. In this report, we show that oenothein B stimulated innate lymphocytes, including bovine and human γδ T cells and NK cells, resulting in either increased CD25 and/or CD69 expression. We also demonstrate that oenothein B enhanced the production of interferon-γ (IFNγ) by bovine and human NK cells alone and in combination with interleukin-18 (IL-18), a response not observed with other commonly studied polyphenols. Furthermore, we demonstrate that oenothein B enhanced the production of IFNγ by human T cells. Since IFNγ contributes to antitumor, antibacterial, and antiviral cell responses, these data suggest an additional mechanism that could account, at least in part, for the immune enhancing properties of oenothein B.

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Oenothein B, a cyclic dimeric ellagitannin isolated from Epilobium angustifolium, enhances IFNγ production by lymphocytes.

γδ T cells are innate lymphocytes that recognize and kill a range of tumor cells and are currently being explored as a target for tumor immunotherapy. However, γδ T cells play a complex role in cancer and can promote, as well as inhibit, tumor growth. In addition to tumor cell killing, γδ T cells express a number of cytokines and other soluble factors in response to tumors. Soluble factors expressed by γδ T cells in these settings include interferon-γ, tumor necrosis factor-α, interleukin (IL)-4, IL-10, transforming growth factor-β, IL-17, and a number of growth factors. These factors have differing and sometimes opposing effects on antitumor immunity and tumor angiogenesis, and likely contribute to the complex role of these cells in cancer. Here, we review studies in both mice and humans that examine differential cytokine secretion by γδ T cells in response to tumors and tumor immunotherapy, and discuss the influence of these γδ T-cell-derived factors on tumor growth.

Complex Role of γδ T-Cell-Derived Cytokines and Growth Factors in Cancer

Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular, primarily pulmonary, bacterial pathogen. Although much is known about adaptive immune responses against this bacterium, our understanding of innate immune responses against C. burnetii is not well defined, particularly within the target tissue for infection, the lung. Previous studies examined the roles of the innate immune system receptors Toll-like receptor 2 (TLR2) and TLR4 in peripheral infection models and described minimal phenotypes in specific gene deletion animals compared to those of their wild-type controls (S. Meghari et al., Ann N Y Acad Sci 1063:161-166, 2005,http://dx.doi.org/10.1196/annals.1355.025; A. Honstettre et al., J Immunol 172:3695-3703, 2004,http://dx.doi.org/10.4049/jimmunol.172.6.3695) . Here, we assessed the roles for TLR2, TLR4, and MyD88 in pulmonary C. burnetii infection and compared responses to those that occurred in TLR2- and TLR4-deficient animals following peripheral infection. As observed previously, neither TLR2 nor TLR4 was needed for limiting bacterial growth after peripheral infection. In contrast, TLR2 and, to a lesser extent, TLR4 limited growth (or dissemination) of the bacterium in the lung and spleen after pulmonary infection. TLR2, TLR4, and MyD88 were not required for the general inflammatory response in the lungs after pulmonary infection. However, MyD88 signaling was important for infection-induced morbidity. Finally, TLR2 expression on hematopoietic cells was most important for limiting bacterial growth in the lung. These results expand on our knowledge of the roles for TLR2 and TLR4 in C. burnetii infection and suggest various roles for these receptors that are dictated by the site of infection.

Andrew Ramstead

Papers

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

Therapeutic Potential of Polyphenols from Epilobium Angustifolium (Fireweed).

Oenothein B, a cyclic dimeric ellagitannin isolated from Epilobium angustifolium, enhances IFNγ production by lymphocytes.

Complex Role of γδ T-Cell-Derived Cytokines and Growth Factors in Cancer

Roles of Toll-Like Receptor 2 (TLR2), TLR4, and MyD88 during Pulmonary Coxiella burnetii Infection