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- Kritikou, Joanna S, et al.
(författare)
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Constitutive activation of WASp leads to abnormal cytotoxic cells with increased granzyme B and degranulation response to target cells.
- 2021
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Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood; however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from 2 patients with XLN harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased granzyme B content and elevated degranulation and IFN-γ production when compared with healthy control cells. Murine WASpL272P NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28-coated beads, respectively. WASpL272P mouse T cells had normal degranulation and cytokine response whereas WASpL272P NK cells showed an enhanced response. Imaging experiments revealed that while WASpL272P CD8+ T cells had increased accumulation of actin upon TCR activation, WASpL272P NK cells had normal actin accumulation at lytic synapses triggered through NKp46 signaling but had impaired response to lymphocyte function associated antigen-1 engagement. When compared with WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I-deficient cells. Together, our data suggest that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells.
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| 3. |
- Sternberg-Simon, M., et al.
(författare)
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Natural killer cell inhibitory receptor expression in humans and mice : A closer look
- 2013
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 4:March, s. 65-
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Tidskriftsartikel (refereegranskat)abstract
- The Natural Killer (NK) cell population is composed of subsets of varying sizes expressing different combinations of inhibitory receptors for MHC class I molecules. Genes within the NK gene complex, including the inhibitory receptors themselves, seem to be the primary intrinsic regulators of inhibitory receptor expression, but the MHC class I background is an additional Modulating factor. In this paper, we have performed a parallel study of the inhibitory receptor repertoire in inbred mice of the C57Bl/6 background and in a cohort of 44 humans. Deviations of subset frequencies from the "product rule (PR)," i.e., differences between observed and expected frequencies of NK cells, were used to identify MHC-independent and MHC-dependent control of receptor expression frequencies. Some deviations from the PR were similar in mice and humans, such as the decreased presence of NK cell subset lacking inhibitory receptors. Others were different, including a role for NKG2A in determining over- or under-representation of specific subsets in humans but not in mice. Thus, while human and murine inhibitory receptor repertoires differed in details, there may also be shared principles governing NK cell repertoire formation in these two species.
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- Abou-Zeid, Nancy, et al.
(författare)
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Towards a cancer mission in Horizon Europe: recommendations
- 2020
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Ingår i: Molecular Oncology. - : Wiley Open Access. - 1878-0261 .- 1574-7891. ; 14:8, s. 1589-1615
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research–care–prevention continuum has the potential to achieve in 2030 a 10-year cancer-specific survival for 75% of patients diagnosed in European Union (EU) member states with a well-developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high-quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science-driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC-like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long-term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans-border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence-based advice.
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| 12. |
- Schepis, D, et al.
(författare)
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Herpes simplex virus infection downmodulates NKG2D ligand expression.
- 2009
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Ingår i: Scandinavian journal of immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 69:5, s. 429-36
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus (HSV) type 1 infection may cause orofacial infections in humans. The virus resides in a latent form in neural ganglia and occasionally reactivates and infects epithelial cells. Natural killer (NK) cells have been implicated in immune control of herpes virus infections, possibly by downmodulating major histocompatibility complex (MHC) class I and by other, as yet unidentified, mechanisms. Upon HSV-1 infection of cell lines, surface levels of NKG2D ligands MHC class I related proteins (MIC) A and UL16 binding protein 2 were downmodulated due to late viral gene product(s). As also MHC class I levels were reduced by HSV-1, NK cell recognition of HeLa cells was not affected by infection. Total cellular MICA contents remained unchanged, suggesting masking, internalization or intracellular retention of MICA as possible mechanisms of viral downregualtion of MICA surface levels. Furthermore, NK cells from patients with active HSV-1 infection had a tendency towards increased expression level of the activating receptor NKG2D. These data support a role for NKG2D-MICA interactions in immune responses to HSV-1 reactivation.
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| 15. |
- Wagner, C. S., et al.
(författare)
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Increased expression of leukocyte Ig-like receptor-1 and activating role of UL18 in the response to cytomegalovirus infection
- 2007
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Ingår i: J Immunol. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 178:6, s. 3536-43
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Tidskriftsartikel (refereegranskat)abstract
- NK and T cells are important for combating CMV infection. Some NK and T cells express leukocyte Ig-like receptor-1 (LIR-1), an inhibitory receptor recognizing MHC class I and the CMV-encoded homolog UL18. We previously demonstrated an early increase in LIR-1-expressing blood lymphocytes in lung-transplanted patients later developing CMV disease. We now show that NK and T cells account for the observed LIR-1 augmentation. Coincubation of PBMC from CMV-seropositive donors with virus-infected lung fibroblasts led to a T cell-dependent secretion of IFN-gamma, produced mainly by LIR-1(+) T cells and by NK cells. Cytokine production during coculture with fibroblasts infected with virus containing the UL18 gene was augmented compared with the UL18 deletion virus, suggesting a stimulatory role for UL18. However, purified UL18Fc proteins inhibited IFN-gamma production of LIR-1(+) T cells. We propose that cytokine production in the transplant induces NK and T cells to express LIR-1, which may predispose to CMV disease by MHC/LIR-1-mediated suppression. Although the UL18/LIR-1 interaction could inhibit T cell responses, this unlikely plays a role in response to infected cells. Instead, our data point to an activating role for viral UL18 during infection, where indirect intracellular effects cannot be excluded.
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