Search results for "Immunologic Surveillance"
showing 10 items of 14 documents
STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity
2020
Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (S…
The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution
2020
The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptid…
Immunosurveillance of lung melanoma metastasis in EBI-3-deficient mice mediated by CD8+ T cells.
2008
Abstract EBV-induced gene 3 (EBI-3) codes for a soluble type I receptor homologous to the p40 subunit of IL-12 that is expressed by APCs following activation. In this study, we assessed the role of EBI-3 in a model of lung melanoma metastasis. Intravenous injection of the B16-F10 cell line resulted in a significant reduction of lung tumor metastasis in EBI-3−/− recipient mice compared with wild-type mice. The immunological finding accompanying this effect was the expansion of a newly described cell subset called IFN-γ producing killer dendritic cells associated with CD8+ T cell responses in the lung of EBI-3−/− mice including IFN-γ release and TNF-α-induced programmed tumor cell death. Depl…
Drp1 Controls Effective T Cell Immune-Surveillance by Regulating T Cell Migration, Proliferation, and cMyc-Dependent Metabolic Reprogramming
2018
Summary Mitochondria are key players in the regulation of T cell biology by dynamically responding to cell needs, but how these dynamics integrate in T cells is still poorly understood. We show here that the mitochondrial pro-fission protein Drp1 fosters migration and expansion of developing thymocytes both in vitro and in vivo. In addition, we find that Drp1 sustains in vitro clonal expansion and cMyc-dependent metabolic reprogramming upon activation, also regulating effector T cell numbers in vivo. Migration and extravasation defects are also exhibited in Drp1-deficient mature T cells, unveiling its crucial role in controlling both T cell recirculation in secondary lymphoid organs and acc…
The gut microbiota - a modulator of endothelial cell function and a contributing environmental factor to arterial thrombosis.
2019
Introduction: There is emerging evidence linking the commensal gut microbiota with the development of cardiovascular disease and arterial thrombosis. In immunothrombosis, the host clotting system protects against the dissemination of invading microbes, not considering the huge number of microbes that interact with host physiology in a mutualistic fashion. Areas covered: Interestingly, recent research revealed that colonizing gut microbes profoundly influence host innate immune pathways that support arterial thrombus growth. The gut microbiota promotes arterial thrombus formation by enhancing the pro-adhesive capacity of the vascular endothelium, triggering hepatic von Willebrand factor synt…
Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance
2002
CD8+ T cells are the main effector cells for the immune control of cytomegaloviruses. To subvert this control, human and mouse cytomegaloviruses each encode a set of immune-evasion proteins, referred to here as immunoevasins, which interfere specifically with the MHC class I pathway of antigen processing and presentation. Although the concerted action of immunoevasins prevents the presentation of certain viral peptides, other viral peptides escape this blockade conditionally or constitutively and thereby provide the molecular basis of immune surveillance by CD8+ T cells. The definition of viral antigenic peptides that are presented despite the presence of immunoevasins adds a further dimens…
Stalemating a clever opportunist: lessons from murine cytomegalovirus.
2003
Abstract Cytomegaloviruses and their specific hosts have come to an arrangement that avoids disease but allows the viruses to persist in the individual host and to spread in the host species. Recent work has uncovered some of the molecular details of this evolutionary “contract for mutual survival.” Cytomegaloviruses encode proteins, referred to as “immunoevasins,” which are specifically committed to subvert the immune defense of the host for evading virus elimination. In reply, the hosts have evolved countermeasures to overcome the viral immunoevasins and present antigenic peptides to an extent that is sufficient for confining virus replication to below a harmful level. Accordingly, cytome…
LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells
2015
Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldhalow) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2-/-γc-/- mice, lacking lymphocytes and NK cells, and in Ifng-/- mice, Ldhalow and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and…
Characterization of human infiltrating and circulating gamma-delta T cells in prostate cancer
2019
Purpose The aim of our study was to prospectively evaluate the distribution of gamma-delta (γδ)1 and γδ2 T cells and their phenotypes in peripheral blood and prostate samples of patients diagnosed with or without prostate cancer (PCa) at prostate biopsy. Materials and methods A consecutive series of 43 outpatients underwent trans-rectal echo-guided prostate biopsy for suspected PCa. Flow cytometry analysis was used to identify and characterize the γδ T cells populations in peripheral blood and tissue samples. Patients were stratified according to the presence or not of PCa, and its International Society of Urological Pathology (ISUP) grade (1 vs. ≥2). Results The distribution of γδ T cells …
Myeloid dendritic cell: From sentinel of immunity to key player of peripheral tolerance?
2009
Myeloid dendritic cells (DC) are "sentinels" of immunity, ideally positioned throughout the body gateways and equipped with unique properties to transport antigens from the periphery to lymphoid tissues. They are professional antigen-presenting cells transmitting incoming infectious signals to T cells, the key players of adaptive immunity. For induction of effective antigen-specific T-cell immunity, crosstalk of DC and naive T cells is mandatory. However, besides this essential immunostimulatory function of DC, consolidated findings from the DC research field in the last 10 years have shown that DC have an additional important function. They act as pivotal players in the peripheral toleranc…