The onset of activation in Th cells is triggered by localized co-engagement of TCRs and the coreceptor CD4. A CD4 crystal suggested that CD4 may form dimers in some circumstances. In this study, we ...use live-cell fluorescence resonance energy transfer imaging to demonstrate that CD4 dimers are present at a basal level on the cell surface and accumulate at the synapse. Mechanistically, we reveal two conditions under which dimers are highly relevant. First, CD4 dimers are more proficient in mediating prolonged cell contacts with APCs in the presence or absence of Ag. This is consistent with a model whereby the dimer functions to increase T-APC avidity. Second, we show that dimer mutations result in an increased level of an inactive lckTyr(505) bound to the CD4 molecule relative to dimer-competent CD4. We also find a consistent defect in signaling onset in these cells. This supports a role for CD4 dimerization in maintaining active signaling machinery. We suggest that modulation of the dimer/monomer ratio may permit tuning of activation thresholds during initial engagement.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development ...of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models
. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.
Introduction Due to their capacity to elicit and regulate immunity, dendritic cells (DCs) are important targets to improve vaccination. Knowing that programmed death-1 (PD-1) high virus-specific T ...cells become functionally exhausted during chronic exposure to human immunodeficiency virus-1 (HIV-1), the development of a therapeutic DC-based HIV-1 vaccine might include strategies that downregulate PD-L1 and PD-L2 counter-receptors. Methods After showing that monocyte-derived DCs rapidly upregulated PD-L1 and PD-L2 expression upon maturation with a variety of stimuli, e.g., Toll-like receptor ligands and cytokines, we determined that PD-L1 and PD-L2 expression could be knocked down by electroporation of a single small interfering RNA (siRNA) sequence twice at the monocyte and immature stages of DC development. This knockdown approached completion and was specific and lasting for several days. Results We then added the PD-L1 and PD-L2 silenced monocyte-derived DCs to peripheral blood mononuclear cells from HIV-1-infected individuals along with pools of 15-mer HIV-1 Gag p24 peptides. However, in cultures from six patients, there was only a modest enhancing effect of PD-L1 and PD-L2 silencing on CD8⁺ T cell proliferative responses to the DCs. Discussion These findings suggest that, in monocyte-derived DCs, additional strategies than PD-L1 or PD-L2 blockade will be needed to improve the function of PD-1 high T cells.
Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic ...cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 μg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.
While local and international NGOs seek to address the crisis facing the Democratic Republic of the Congo, perpetrators of human rights crimes are still largely able to avoid being brought to ...justice. Gaelle Breton-Le Goff, Lecturer in International Human Rights Law at the University of Quebec, outlines the driving forces behind the massive sexual violence and proposes key social, legal, and diplomatic approaches for international policymakers.
Intranasal (i.n.) vaccination generates immunity across local, regional, and distant sites. However, nasal dendritic cells (DCs), pivotal for the induction of i.n. vaccine-induced immune responses, ...have not been studied in detail. Here, by using a variety of parameters, we define nasal DCs in mice and humans. Distinct subsets of "classical" DCs, dependent on the transcription factor zbtb46 were identified in the murine nose. The murine nasal DCs were Fms-related tyrosine 3 kinase ligand responsive and displayed unique phenotypic and functional characteristics, including the ability to present antigen, induce an allogeneic T-cell response, and migrate in response to lipopolysaccharide or live bacterial pathogens. Importantly, in a cohort of human volunteers, BDCA-1(+) DCs were observed to be the dominant nasal DC population at steady state. During chronic inflammation, the frequency of both BDCA-1(+) and BDCA-3(hi) DCs was reduced in the nasal tissue, associating the loss of these immune sentinels with chronic nasal inflammation. The present study is the first detailed description of the phenotypic, ontogenetic, and functional properties of nasal DCs, and will inform the design of preventative immunization strategies as well as therapeutic modalities against chronic rhinosinusitis.
PURPOSE OF REVIEWThe intricate balance between positive and negative signals delivered by accessory molecules is crucial to generate efficient immune responses while maintaining tolerance and ...preventing autoimmunity. Of these molecules, programmed death 1 has been described as a negative regulator of T-cell activation. This review will focus on current knowledge about PD-1 regulation in different diseases and discuss its potential benefits for the development of novel immune therapies.
RECENT FINDINGSPD-1 has recently been shown to be upregulated on HIV-specific CD8 T cells, whereas the PD-1 expression level was significantly correlated with viral load. Blockade of the PD-1/PD-L1 interaction enhanced the capacity of HIV-specific CD8 and CD4 T cells to proliferate or secrete cytokines and cytotoxic molecules. Future manipulations of this pathway could rescue the function of exhausted CD8 and CD4 T cells.
SUMMARYThe engagement of PD-1 with its ligands induces inhibitory signals as it blocks T-cell receptor-induced T-cell proliferation and cytokine production. The PD-1 pathway plays a crucial role in the maintenance of peripheral tolerance and the pathogenesis of cancer and chronic viral infections. Understanding the mechanisms by which PD-1 interferes with T-cell functions will pave the way for novel therapeutic immune interventions to treat these diseases.
Hole-conjugate states of the fractional quantum Hall effect host counter-propagating edge channels which are thought to exchange charge and energy. These exchanges have been the subject of extensive ...theoretical and experimental works; in particular, it is yet unclear if the presence of integer quantum Hall edge channels stemming from fully filled Landau levels affects heat equilibration along the edge. In this letter, we present heat transport measurements in quantum Hall states of graphene demonstrating that the integer channels can strongly equilibrate with the fractional ones, leading to markedly different regimes of quantized heat transport that depend on edge electrostatics. Our results allow for a better comprehension of the complex edge physics in the fractional quantum Hall regime.
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