CD152 (CTLA-4) Determines CD4 T Cell Migration In Vitro and In Vivo

BACKGROUND:Migration of antigen-experienced T cells to secondary lymphoid organs and the site of antigenic-challenge is a mandatory prerequisite for the precise functioning of adaptive immune responses. The surface molecule CD152 (CTLA-4) is mostly considered as a negative regulator of T cell activation during immune responses. It is currently unknown whether CD152 can also influence chemokine-driven T cell migration. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed the consequences of CD152 signaling on Th cell migration using chemotaxis assays in vitro and radioactive cell tracking in vivo. We show here that the genetic and serological inactivation of CD152 in Th1 cells reduced migration towards CCL4, CXCL12 and CCL19, but not CXCL9, in a G-protein dependent manner. In addition, retroviral transduction of CD152 cDNA into CD152 negative cells restored Th1 cell migration. Crosslinking of CD152 together with CD3 and CD28 stimulation on activated Th1 cells increased expression of the chemokine receptors CCR5 and CCR7, which in turn enhanced cell migration. Using sensitive liposome technology, we show that mature dendritic cells but not activated B cells were potent at inducing surface CD152 expression and the CD152-mediated migration-enhancing signals. Importantly, migration of CD152 positive Th1 lymphocytes in in vivo experiments increased more than 200% as compared to CD152 negative counterparts showing that indeed CD152 orchestrates specific migration of selected Th1 cells to sites of inflammation and antigenic challenge in vivo. CONCLUSIONS/SIGNIFICANCE:We show here, that CD152 signaling does not just silence cells, but selects individual ones for migration. This novel activity of CD152 adds to the already significant role of CD152 in controlling peripheral immune responses by allowing T cells to localize correctly during infection. It also suggests that interference with CD152 signaling provides a tool for altering the cellular composition at sites of inflammation and antigenic challenge

Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines

The field of tumor vaccination is currently undergoing a shift in focus, from individualized tailor-made vaccines to more generally applicable vaccine formulations. Although primarily predicated by financial and logistic considerations, stemming from a growing awareness that clinical development for wide-scale application can only be achieved through backing from major pharmaceutical companies, these new approaches are also supported by a growing knowledge of the intricacies and minutiae of antigen presentation and effector T-cell activation. Here, the development of whole-cell tumor and dendritic cell (DC)-based vaccines from an individualized autologous set-up to a more widely applicable allogeneic approach will be discussed as reflected by translational studies carried out over the past two decades at our laboratories and clinics in the vrije universiteit medical center (VUmc) in Amsterdam, The Netherlands

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity

The structure of heated tool weld seams

Translated from German (Proc. Conf. Welding and Adhesive Bonding of Plastics, Dusseldorf, 1983)SIGLEAvailable from British Library Lending Division - LD:9312.57(WI-Trans--701)T / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The comparison of macroseismic intensity scales

The number of different macroseismic scales that have been used to express earthquake shaking in the course of the last 200 years is not known; it may reach three figures. The number of important scales that have been widely adopted is much smaller, perhaps about eight, not counting minor variants. Where data sets exist that are expressed in different scales, it is often necessary to establish some sort of equivalence between them, although best practice would be to reassign intensity values rather than convert them. This is particularly true because difference between workers in assigning intensity is often greater than differences between the scales themselves, particularly in cases where one scale may not be very well defined. The extent to which a scale guides the user to arrive at a correct assessment of the intensity is a measure of the quality of the scale. There are a number of reasons why one should prefer one scale to another for routine use, and some of these tend in different directions. If a scale has many tests (diagnostics) for each degree, it is more likely that the scale can be applied in any case that comes to hand, but if the diagnostics are so numerous that they include ones that do not accurately indicate any one intensity level, then the use of the scale will tend to produce false values. The purpose of this paper is chiefly to discuss in a general way the principles involved in the analysis of intensity scales. Conversions from different scales to the European Macroseismic Scale are discussed