Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans.

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.

Antibody response to three-dose anti-SARS-CoV-2 mRNA-vaccination in treated solid cancer patients.

Solid cancer patients are at higher risk of SARS-CoV-2 infection and severe complications. Moreover, vaccine-induced antibody response is impaired in patients on anticancer treatment. In this retrospective, observational, hypothesis-generating, cohort study, we assessed the antibody response to the third dose of mRNA vaccine in a convenience sample of patients on anticancer treatment, comparing it to that of the primary two-dose cycle. Among 99 patients included, 62.6% were ≥60 years old, 32.3% males, 67.7% with advanced disease. Exactly 40.4% were receiving biological therapy, 16.2% chemotherapy only and 7.1% both treatments. After the third dose, seroconversion rate seems to increase significantly, especially in non-responders to two doses. Heterologous vaccine-type regimen (two-dose mRNA-1273 and subsequent tozinameran or vice versa) results in higher antibody levels. This explorative study suggests that repeated doses of mRNA-vaccines could be associated with a better antibody response in this population. Furthermore, heterologous vaccine-type three-dose vaccination seems more effective in this population. Since this is a hypothesis-generating study, adequately statistically powered studies should validate these results.

What do we mean by long COVID? A scoping review of the cognitive sequelae of SARS-CoV-2 infection.

BACKGROUND AND PURPOSE: Many COVID-19 patients report persistent symptoms, including cognitive disturbances. We performed a scoping review on this topic, focusing primarily on cognitive manifestations. METHODS: Abstracts and full texts of studies published on PubMed (until May 2023) addressing cognitive involvement persisting after SARS-CoV-2 infection were reviewed, focusing on terms used to name the cognitive syndrome, reported symptoms, their onset time and duration, and testing batteries employed. Reported psychiatric symptoms, their assessment tools, and more general manifestations were also extracted. RESULTS: Among the 947 records identified, 180 studies were included. Only one third of them used a label to define the syndrome. A minority of studies included patients according to stringent temporal criteria of syndrome onset (34%), whereas more studies reported a minimum required symptom duration (77%). The most frequently reported cognitive symptoms were memory and attentional-executive disturbances, and among psychiatric complaints, the most frequent were anxiety symptoms, depression, and sleep disturbances. Most studies reported fatigue among general symptoms. Thirty-six studies employed cognitive measures: screening tests alone (n = 19), full neuropsychological batteries (n = 25), or both (n = 29); 30 studies performed psychiatric testing. Cognitive deficits were demonstrated in 39% of subjects, the most frequently affected domains being attention/executive functions (90%) and memory (67%). CONCLUSIONS: Currently, no agreement exists on a label for post-COVID-19 cognitive syndrome. The time of symptom onset after acute infection and symptom duration are still discussed. Memory and attention-executive complaints and deficits, together with fatigue, anxiety, and depression symptoms, are consistently reported, but the objective evaluation of these symptoms is not standardized.

NK cells to cure cancer.

Natural Killer (NK) cells are innate lymphocytes able to mediate immune-surveillance and clearance of viral infected and tumor-transformed cells. Growing experimental and clinical evidence highlighted a dual role of NK cells either in the control of cancer development/progression or in promoting the onset of immune-suppressant tumor microenvironments. Indeed, several mechanisms of NK cell-mediated tumor escape have been described and these includes cancer-induced aberrant expression of activating and inhibitory receptors (i.e. NK cell immune checkpoints), impairments of NK cell migration to tumor sites and altered NK cell effector-functions. These phenomena highly contribute to tumor progression and metastasis formation. In this review, we discuss the latest insights on those NK cell receptors and related molecules that are currently being implemented in clinics either as possible prognostic factors or therapeutic targets to unleash NK cell anti-tumor effector-functions in vivo. Moreover, we address here the major recent advances in regard to the genetic modification and ex vivo expansion of anti-tumor specific NK cells used in innovative adoptive cellular transfer approaches.

Interaction of Bacteria, Immune Cells, and Surface Topography in Periprosthetic Joint Infections.

The incidence of periprosthetic joint infections (PJIs) is ~2% of total procedures and it is expected to rise due to an ageing population. Despite the large burden PJI has on both the individual and society, the immune response to the most commonly isolated pathogens, i.e., Staphylococcus aureus and Staphylococcus epidermidis, remains incompletely understood. In this work, we integrate the analysis of synovial fluids from patients undergoing hip and knee replacement surgery with in-vitro experimental data obtained using a newly developed platform, mimicking the environment of periprosthetic implants. We found that the presence of an implant, even in patients undergoing aseptic revisions, is sufficient to induce an immune response, which is significantly different between septic and aseptic revisions. This difference is confirmed by the presence of pro- and anti-inflammatory cytokines in synovial fluids. Moreover, we discovered that the immune response is also dependent on the type of bacteria and the topography of the implant surface. While S. epidermidis seems to be able to hide better from the attack of the immune system when cultured on rough surfaces (indicative of uncemented prostheses), S. aureus reacts differently depending on the contact surface it is exposed to. The experiments we performed in-vitro also showed a higher biofilm formation on rough surfaces compared to flat ones for both species, suggesting that the topography of the implant could influence both biofilm formation and the consequent immune response.

Comprehensive Phenotyping of Dendritic Cells in Cancer Patients by Flow Cytometry.

Dendritic cells (DCs) play a crucial role in the complex interplay between tumor cells and the immune system. During the elimination phase of cancer immunoediting, immunostimulatory DCs are critical for the control of tumor growth. During the escape phase, regulatory DCs sustain tumor tolerance and contribute to the development of the immunosuppressive tumor microenvironment that characterizes this phase. Moreover, increasing evidence indicates that DCs are also critical for the success of cancer immunotherapy. Hence, there is increasing need to fully characterize DC subsets and their activatory/inhibitory profile in cancer patients. In this review, we describe the role played by different DC subsets in the different phases of cancer immunoediting, the function exerted by different activatory and inhibitory molecules expressed on DC surface, and the cytokines produced by distinct DC subsets, in order to provide an overview on the DC features that may be useful to be assessed when dealing with the flow cytometric characterization of DCs in cancer patients. © 2020 International Society for Advancement of Cytometry.

CXCR3 Identifies Human Naive CD8+ T Cells with Enhanced Effector Differentiation Potential.

In mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells.

The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling.

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.

APOL1 polymorphism modulates sphingolipid profile of human podocytes.

Apolipoprotein L1 (APOL1) wild type (G0) plays a role in the metabolism of sphingolipids, glycosphingolipids, sphingomyelin and ceramide, which constitute bioactive components of the lipid rafts (DRM). We asked whether APOL1 variants (APOL1-Vs) G1 and G2 carry the potential to alter the metabolism of sphingolipids in human podocytes. The sphingolipid pattern in HPs overexpressing either APOL1G0 or APOL1-Vs was analysed by using a thin mono- and bi-dimensional layer chromatography, mass-spectrometry and metabolic labelling with [1-3H]sphingosine. HP G0 and G1/G2-Vs exhibit a comparable decrease in lactosylceramide and an increase in the globotriaosylceramide content. An analysis of the main glycohydrolases activity involved in glycosphingolipid catabolism showed an overall decrease in the activeness of the tested enzymes, irrespective of the type of APOL1-Vs expression. Similarly, the high throughput cell live-based assay showed a comparable increased action of the plasma membrane glycosphingolipid-glycohydrolases in living cells independent of the genetic APOL1 expression profile. Importantly, the most significative modification of the sphingolipid pattern induced by APOL1-Vs occurred in DRM resulted with a drastic reduction of radioactivity associated with sphingolipids. G1/G2-Vs present a decrease amount of globotriaosylceramide and globopentaosylceramide compared to G0. Additionally, ceramide at the DRM site and lactosylceramide in general, showed a greatest fall in G1/G2 in comparison with G0. Additionally, the levels of glucosylceramide decreased only in the DRM of human podocytes overexpressing G1/G2-Vs. These findings suggest that altered sphingolipidsprofiles may contribute to the deranged functionality of the plasma membrane in APOL1 risk milieu.