Human Vδ2+ γδ T cells differentially induce maturation, cytokine production, and alloreactive T cell stimulation by dendritic cells and B cells

Human ?? T cells expressing the V?9V?2 T cell receptor can induce maturation of dendritic cells (DC) into antigen-presenting cells (APC) and B cells into antibody-secreting plasma cells. Since B cells are capable of presenting antigens to T cells, we investigated if V?9V?2 T cells can influence antigen-presentation by these cells. We report that V?9V?2 T cells induced expression of CD86, HLA-DR, and CD40 by B cells and stimulated the release of IL-4, IL-6, TNF-?, and IgG, IgA, and IgM. V?9V?2 T cells also augmented the ability of B cells to stimulate proliferation but not IFN-? or IL-4 release by alloreactive T cells. In contrast, V?9V?2 T cells induced expression of CD86 and HLA-DR and the release of IFN-?, IL-6, and TNF-? by DC and these DC stimulated proliferation and IFN-? production by conventional T cells. Furthermore, CD86, TNF-?, IFN-?, and cell contact were found to be important in DC activation by V?9V?2 T cells but not in the activation of B cells. These data suggest that V?9V?2 T cells can induce maturation of B cells and DC into APC, but while they prime DC to stimulate T helper 1 (TH1) responses, they drive maturation of B cells into APC that can stimulate different T cell responses. Thus, V?9V?2 T cells can control different arms of the immune system through selective activation of B cells and DC in vitro, which may have important applications in immunotherapy and for vaccine adjuvants

Differential regulation of human Treg and Th17 cells by fatty acid synthesis and glycolysis

In this study we examined the metabolic requirements of human T helper cells and the effect of manipulating metabolic pathways in Th17 and Treg cells. The Th17:Treg cell axis is dysregulated in a number of autoimmune or inflammatory diseases and therefore it is of key importance to identify novel strategies to modulate this axis in favor of Treg cells. We investigated the role of carbohydrate and fatty acid metabolism in the regulation of human memory T helper cell subsets, in order to understand how T cells are regulated at the site of inflammation where essential nutrients including oxygen may be limiting. We found that Th17 lineage cells primarily utilize glycolysis, as glucose-deprivation and treatment with rapamycin resulted in a reduction in these cells. On the other hand, Treg cells exhibited increased glycolysis, mitochondrial respiration, and fatty acid oxidation, whereas Th17 cells demonstrated a reliance upon fatty acid synthesis. Treg cells were somewhat reliant on glycolysis, but to a lesser extent than Th17 cells. Here we expose a fundamental difference in the metabolic requirements of human Treg and Th17 cells and a possible mechanism for manipulating the Th17: Treg cell axis

Human Macrophages Activate Bystander Neutrophils’ Metabolism and Effector Functions When Challenged with <i>Mycobacterium tuberculosis</i>

Neutrophils are dynamic cells, playing a critical role in pathogen clearance; however, neutrophil infiltration into the tissue can act as a double-edged sword. They are one of the primary sources of excessive inflammation during infection, which has been observed in many infectious diseases including pneumonia and active tuberculosis (TB). Neutrophil function is influenced by interactions with other immune cells within the inflammatory lung milieu; however, how these interactions affect neutrophil function is unclear. Our study examined the macrophage–neutrophil axis by assessing the effects of conditioned medium (MΦ-CM) from primary human monocyte-derived macrophages (hMDMs) stimulated with LPS or a whole bacterium (Mycobacterium tuberculosis) on neutrophil function. Stimulated hMDM-derived MΦ-CM boosts neutrophil activation, heightening oxidative and glycolytic metabolism, but diminishes migratory potential. These neutrophils exhibit increased ROS production, elevated NET formation, and heightened CXCL8, IL-13, and IL-6 compared to untreated or unstimulated hMDM-treated neutrophils. Collectively, these data show that MΦ-CM from stimulated hMDMs activates neutrophils, bolsters their energetic profile, increase effector and inflammatory functions, and sequester them at sites of infection by decreasing their migratory capacity. These data may aid in the design of novel immunotherapies for severe pneumonia, active tuberculosis and other diseases driven by pathological inflammation mediated by the macrophage–neutrophil axis

Novel thioglycoside analogs of ?-galactosylceramide stimulate cytotoxicity and preferential Th1 cytokine production by human invariant natural killer T cells

Invariant natural killer T (iNKT) cells recognize glycolipid antigens bound to CD1d molecules on antigen-presenting cells. Therapeutic activation of iNKT cells with the xenogeneic glycolipid ?-galactosylceramide (?-GalCer) can prevent and reverse tumor growth in murine models, but clinical trials using ?-GalCer-stimulated human iNKT cells have shown limited efficacy. We synthesized a series of thioglycoside analogs of ?-GalCer with different substituents to the galactose residue and found that two of these compounds, XZ7 and XZ11, bound to CD1d-transfected HeLa cells and activated lines of expanded human iNKT cells. Both compounds stimulated cytolytic degranulation by iNKT cells and while XZ7 preferentially stimulated the production of the antitumor cytokine interferon-? (IFN-?), XZ11 preferentially stimulated interleukin-4 (IL-4) production. This biased T helper type 1 effector profile of XZ7 was also evident when iNKT were stimulated with dendritic cells presenting this glycolipid. Separate analysis of the responses of CD4+, CD8?+ and CD4?CD8? iNKT cells indicated that XZ7 preferentially activated CD8?+ iNKT cells, and to a lesser degree, CD4?CD8? iNKT cells. The partial agonist effect of glycolipid XZ7, inducing cytotoxicity and IFN-? production but not IL-4 production, indicates that specific protumour activities of iNKT cells can be abolished, while preserving their antitumor activities, by introducing structural modifications to ?-GalCer. Since XZ7 was much less potent than ?-GalCer as an iNKT cell agonist, it is unlikely to be superior to ?-GalCer as a therapeutic agent for cancer, but may serve as a parent compound for developing more potent structural analogs