IL-15 produced and trans-presented by DCs underlies homeostatic competition between CD8 and {gamma}{delta} T cells in vivo.
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ABSTRACT:
SUBMITTER: Do JS
PROVIDER: S-EPMC2710929 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dendritic cell (DC) vaccination can be an effective post-remission therapy for acute myeloid leukemia (AML). Yet, current DC vaccines do not encompass the ideal stimulatory triggers for innate gamma delta (??) T cell anti-tumor activity. Promoting type 1 cytotoxic ?? T cells in patients with AML is, however, most interesting, considering these unconventional T cells are primed for rapid function and exert meaningful control over AML. In this work, we demonstrate that interleukin (IL)-15 DCs have the capacity to enhance the anti-tumoral functions of ?? T cells. IL-15 DCs of healthy donors and of AML patients in remission induce the upregulation of cytotoxicity-associated and co-stimulatory molecules on the ?? T cell surface, but not of co-inhibitory molecules, incite ?? T cell proliferation and stimulate their interferon-? production in the presence of blood cancer cells and phosphoantigens. Moreover, the innate cytotoxic capacity of ?? T cells is significantly enhanced upon interaction with IL-15 DCs, both towards leukemic cell lines and allogeneic primary AML blasts. Finally, we address soluble IL-15 secreted by IL-15 DCs as the main mechanism behind the IL-15 DC-mediated ?? T cell activation. These results indicate that the application of IL-15-secreting DC subsets could render DC-based anti-cancer vaccines more effective through, among others, the involvement of ?? T cells in the anti-leukemic immune response.
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Project description:We propose a mechanism for tumor growth emphasizing the role of homeostatic regulation and tissue stability. We show that competition between surface and bulk effects leads to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property can qualitatively explain the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. In addition, it potentially explains the observed preferential growth of metastases on tissue surfaces and membranes such as the pleural and peritoneal layers, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889, and yields realistic values for metastatic inefficiency. We propose a number of key experiments to test these concepts. The homeostatic pressure as introduced in this work could constitute a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.
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Project description:Data Access Committee EGAC00001003406
| EGAC00001003406 | EGA
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Project description:The gammadelta T cells are prevalent in the mucosal epithelia and are postulated to act as 'sentries' for maintaining tissue integrity. What these gammadelta T cells recognize is poorly defined, but given the restricted T cell receptor (TCR) repertoire, the idea that they are selected by self antigens of low complexity has been widely disseminated. Here we present data showing that the generation of the restricted TCR variable gamma-region gene repertoire of intestinal intraepithelial lymphocytes was regulated by interleukin 15, which induced local chromatin modifications specific for the variable gamma-region gene segment and enhanced accessibility conducive to subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation probably reflects distinct TCR repertoire selection criteria for gammadelta and alphabeta T cell lineages adopted for different antigen-recognition strategies.
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Project description:The replay of previously stored memories during hippocampal sharp wave ripples (SWRs) is thought to support both memory retrieval and consolidation in distributed hippocampal-neocortical circuits. Replay events consist of precisely timed sequences of spikes from CA3 and CA1 neurons that are coordinated both within and across hemispheres. The mechanism of this coordination is not understood. Here, we show that during SWRs in both awake and quiescent states there are transient increases in slow gamma (20-50 Hz) power and synchrony across dorsal CA3 and CA1 networks of both hemispheres. These gamma oscillations entrain CA3 and CA1 spiking. Moreover, during awake SWRs, higher levels of slow gamma synchrony are predictive of higher quality replay of past experiences. Our results indicate that CA3-CA1 gamma synchronization is a central component of awake memory replay and suggest that transient gamma synchronization serves as a clocking mechanism to enable coordinated memory reactivation across the hippocampal network.
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Project description:BACKGROUND: Extracellular domains of the Notch family of signalling receptors contain many EGF repeat domains, as do their major ligands. Some EGF repeats are modified by O-fucosylation, and most have no identified role in ligand binding. RESULTS: Using a binding assay with purified proteins in vitro, it was determined that, in addition to binding to Delta, the ligand binding region of Notch bound to EGF repeats 22-27 of Notch, but not to other EGF repeat regions of Notch. EGF repeats 22-27 of Drosophila Notch overlap the genetically-defined 'Abruptex' region, and competed with Delta for binding to proteins containing the ligand-binding domain. Delta differed from the Abruptex domain in showing markedly enhanced binding at acid pH. Both Delta and the Abruptex region are heavily modified by protein O-fucosylation, but the split mutation of Drosophila Notch, which affects O-fucosylation of EGF repeat 14, did not affect binding of Notch to either Delta or the Abruptex region. CONCLUSION: The Abruptex region may serve as a barrier to Notch activation by competing for the ligand-binding domain of Notch.
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