Mögliche Auswirkungen des neu vom Bundesverfassungsgericht in Recht auf Vergessen I und Recht auf Vergessen II eingeführten Konzepts auf das Strafrecht

Dieser Beitrag ist mit Zustimmung des Rechteinhabers (De Gruyter) frei zugänglich.Peer Reviewe

Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases

Computational decomposition reveals reshaping of the SARS‐CoV‐2–ACE2 interface among viral variants expressing the N501Y mutation

Abstract Variants of concern of the SARS‐CoV‐2 virus with an asparagine‐to‐tyrosine substitution at position 501 (N501Y) in the receptor‐binding domain (RBD) show enhanced infectivity compared to wild‐type, resulting in an altered pandemic situation in affected areas. These SARS‐Cov‐2 variants comprise the two Alpha variants (B.1.1.7, United Kingdom and B.1.1.7 with the additional E484K mutation), the Beta variant (B.1.351, South Africa), and the Gamma variant (P.1, Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows to depict changes, but also common motifs of virus–host cell interaction. The trimeric spike protein expressed at the viral surface contains the RBD that forms the molecular interface with ACE2. All the above‐mentioned variants carry between one and three amino acid exchanges within the interface‐forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics (MD) simulations and decomposition of intermolecular contacts between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500, and tyrosine 505 as important interface‐forming residues across viral variants. However, especially the N501Y exchange increased contact formation for this residue and also induced some local conformational changes. Comparing here, the in silico generated B.1.1.7 RBD–ACE2 complex with the now available experimentally solved structure reveals very similar behavior during MD simulation. We demonstrate, how computational methods can help to identify differences in conformation as well as contact formation for newly emerging viral variants. Altogether, we provide extensive data on all N501Y expressing SARS‐CoV‐2 variants of concern with respect to their interaction with ACE2 and how this induces reshaping of the RBD–ACE2 interface

Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide

The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD–ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD–ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7

XCR1 expression distinguishes human conventional dendritic cell type 1 with full effector functions from their immediate precursors

Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1$^{-}$ and XCR1$^{+}$ cDC1 in lymphoid as well as nonlymphoid tissues. Steady-state XCR1$^{+}$ cDC1 display a preactivated phenotype compared to XCR1$^{-}$ cDC1. Upon stimulation, XCR1$^{+}$ cDC1, but not XCR1$^{-}$ cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1$^{+}$ cDC1. Moreover, XCR1$^{+}$ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1$^{-}$ cDC1 developed into XCR1$^{+}$ cDC1. After acquisition of XCR1 expression, XCR1$^{-}$ cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1$^{-}$ cDC1 seem to represent a late immediate precursor of cDC1

Monocytes Elicit a Neutrophil-Independent Th1/Th17 Response Upon Immunization With a Mincle-Dependent Glycolipid Adjuvant

Successful subunit vaccination with recombinant proteins requires adjuvants. The glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization. TDB binds to the C-type lectin receptor Mincle and triggers Syk-Card9-dependent APC activation. In addition, interleukin (IL)-1 receptor/MyD88-dependent signaling is required for TDB adjuvanticity. The role of different innate immune cell types in adjuvant-stimulated Th1/Th17 responses is not well characterized. We investigated cell recruitment to the site of injection (SOI) and to the draining lymph nodes (dLNs) after immunization with the TDB containing adjuvant CAF01 in a protein-based vaccine. Recruitment of monocytes and neutrophils to the SOI and the dramatic increase in lymph node cellularity was partially dependent on both Mincle and MyD88. Despite their large numbers at the SOI, neutrophils were dispensable for the induction of Th1/Th17 responses. In contrast, CCR2-dependent monocyte recruitment was essential for the induction of Th1/Th17 cells. Transport of adjuvant to the dLN did not require Mincle, MyD88, or CCR2. Together, adjuvanticity conferred by monocytes can be separated at the cellular level from potential tissue damage by neutrophils

In situ investigation of the cytotoxic and interfacial characteristics of titanium when galvanically coupled with magnesium using scanning electrochemical microscopy

Recently, the cytotoxic properties of galvanically coupled Mg-Ti particles have been shown to different cells, although this cytotoxic effect has been attributed mainly to Mg due to its tendency to undergo activation when coupled with Ti forming a galvanic cell consisting of an anode (Mg) and a cathode (Ti). However, the role of the Ti cathode has been ignored in explaining the cytotoxic effect of Mg-Ti particles due to its high resistance to corrosion. In this work, the role of titanium (Ti) in the cytotoxic mechanism of galvanically coupled Mg-Ti particles was examined. A model galvanic cell was prepared to simulate the Mg-Ti particles. The electrochemical reactivity of the Ti sample and the pH change above it due to galvanic coupling with Mg were investigated using scanning electrochemical microscopy (SECM). It was observed that the Ti surface changed from passive to electrochemically active when coupled with Mg. Furthermore, after only 15 min galvanic coupling with Mg, the pH in the electrolyte volume adjacent to the Ti surface increased to an alkaline pH value. The effects of the galvanic coupling of Ti and Mg, as well as of the alkaline pH environment, on the viability of Hs27 fibroblast cells were investigated. It was shown that the viability of Hs27 cells significantly diminished when Mg and Ti were galvanically coupled compared to when the two metals were electrically disconnected. Next, the generation of reactive oxygen species (ROS) increased when the Ti and Mg were galvanically coupled. Thus, although Ti usually exhibited high corrosion resistance when exposed to physiological environments, an electrochemically active surface was observed when galvanically coupled with Mg, and this surface may participate in electron transfer reactions with chemical species in the neighboring environment; this participation resulted in the increased pH values above its surface and enhanced generation of ROS. These features contributed to the development of cytotoxic effects by galvanically coupled Mg-Ti particles

Impaired gp100-Specific CD8(+) T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model.

Murine tumor models that closely reflect human diseases are important tools to investigate carcinogenesis and tumor immunity. The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In the present study, we characterized the immune status and functional properties of immune cells in tumor-bearing mice. Melanoma development was accompanied by a reduction in the percentages of CD4(+) T cells including regulatory T cells (Tregs) in CD45(+) leukocytes present in tumor tissue and draining lymph nodes (LNs). In contrast, the percentages of CD8(+) T cells were unchanged, and these cells showed an activated phenotype in tumor mice. Endogenous melanoma-associated antigen glycoprotein 100 (gp100)-specific CD8(+) T cells were not deleted during tumor development, as revealed by pentamer staining in the skin and draining LNs. They, however, were unresponsive to ex vivo gp100-peptide stimulation in late-stage tumor mice. Interestingly, immunosuppressive myeloid-derived suppressor cells (MDSCs) were recruited to tumor tissue with a preferential accumulation of granulocytic MDSC (grMDSCs) over monocytic MDSC (moMDSCs). Both subsets produced Arginase-1, inducible nitric oxide synthase (iNOS), and transforming growth factor-β and suppressed T-cell proliferation in vitro. In this work, we describe the immune status of a spontaneous melanoma mouse model that provides an interesting tool to develop future immunotherapeutical strategies.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov't2015 Nov2015 06 29importe