Learning the sequence code of protein expression in human immune cells.

Accurate protein expression in human immune cells is essential for appropriate cellular function. The mechanisms that define protein abundance are complex and are executed on transcriptional, posttranscriptional, and posttranslational levels. Here, we present SONAR, a machine learning pipeline that learns the endogenous sequence code and that defines protein abundance in human cells.

Increased effector memory CD4 T cells are associated with chronic childhood immune thrombocytopenia.

Background: Antibody- and T-cell immune responses against platelet self-antigens are key features of childhood immune thrombocytopenia (ITP). Reliable diagnostic and prognostic immune markers remain underdeveloped and are not currently used in clinical practice.

Objectives: To validate previously suggested biomarkers and identify novel predictors of chronic childhood ITP.

Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products.

Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has proven highly effective for treating solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy for yet unknown reasons. Defining markers that correlate with high tumor-reactivity of the autologous TIL products is thus key for achieving better tailored immunotherapies.

Gene and protein sequence features augment HLA class I ligand predictions.

The sensitivity of malignant tissues to T cell-based immunotherapies depends on the presence of targetable human leukocyte antigen (HLA) class I ligands. Peptide-intrinsic factors, such as HLA class I affinity and proteasomal processing, have been established as determinants of HLA ligand presentation. However, the role of gene and protein sequence features as determinants of epitope presentation has not been systematically evaluated.

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.

2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8 T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function.

Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function.

Potent T cell responses against infections and malignancies require a rapid yet tightly regulated production of toxic effector molecules. Their production level is defined by post-transcriptional events at 3' untranslated regions (3' UTRs). RNA binding proteins (RBPs) are key regulators in this process.

Re-use of laboratory utensils reduces CO2 equivalent footprint and running costs.

Laboratory-based research is resource intensive in terms of financial costs and its carbon footprint. Research laboratories require immense amounts of energy to power equipment, as well as large volumes of materials, particularly of single-use item consumption. In fact, many laboratories have essentially become reliant on single-use plastics.

The relationship of mRNA with protein expression in CD8+ T cells associates with gene class and gene characteristics.

T cells are key players in our defence against infections and malignancies. When T cells differentiate or become activated, they undergo substantial alterations in gene expression. Even though RNA expression levels are now well documented throughout different stages of T cells, it is not well understood how mRNA expression translates into the protein landscape.

RNA-Binding Protein Expression Alters Upon Differentiation of Human B Cells and T Cells.

B cells and T cells are key players in the defence against infections and malignancies. To exert their function, B cells and T cells differentiate into effector and memory cells. Tight regulation of these differentiation processes is key to prevent their malfunction, which can result in life-threatening disease.

CD29 Enriches for Cytotoxic Human CD4 T Cells.

CD4 T cells are key contributors in the induction of adaptive immune responses against pathogens. Even though CD4 T cells are primarily classified as noncytotoxic helper T cells, it has become appreciated that a subset of CD4 T cells is cytotoxic. However, tools to identify these cytotoxic CD4 T cells are lacking.

Circular RNAs exhibit limited evidence for translation, or translation regulation of the mRNA counterpart in terminal hematopoiesis.

Each day, about 10 erythrocytes and platelets are released into the bloodstream. This substantial output from hematopoietic stem cells is tightly regulated by transcriptional and epigenetic factors. Whether and how circular RNAs (circRNAs) contribute to the differentiation and/or identity of hematopoietic cells is to date not known.

Sequence determinants as key regulators in gene expression of T cells.

T cell homeostasis, T cell differentiation, and T cell effector function rely on the constant fine-tuning of gene expression. To alter the T cell state, substantial remodeling of the proteome is required. This remodeling depends on the intricate interplay of regulatory mechanisms, including post-transcriptional gene regulation.

CD29 identifies IFN-γ-producing human CD8 T cells with an increased cytotoxic potential.

Cytotoxic CD8 T cells can effectively kill target cells by producing cytokines, chemokines, and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and preselect CD8 T cells with a cytotoxic expression profile are lacking. Human CD8 T cells can be divided into IFN-γ- and IL-2-producing cells.

Combined Single-Cell Measurement of Cytokine mRNA and Protein in Immune Cells.

A key feature of immune cells, such as T cells, is their rapid responsiveness to activation. The response rate of T cells depends on the signal strength, and the type of signals they receive. Studying the underlying mechanisms that define responsiveness, however, is confounded by the fact that immune cells do not uniformly respond to activation.

Polyfunctional tumor-reactive T cells are effectively expanded from non-small cell lung cancers, and correlate with an immune-engaged T cell profile.

Non-small cell lung cancer (NSCLC) is the second most prevalent type of cancer. With the current treatment regimens, the mortality rate remains high. Therefore, better therapeutic approaches are necessary.

Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR.

Growing evidence indicate that large antigen-containing particles induce potent T cell-dependent high-affinity antibody responses. These responses require large particle internalization after recognition by the B cell receptor (BCR) on B cells. However, the molecular mechanisms governing BCR-mediated internalization remain unclear.

Critical role of post-transcriptional regulation for IFN-γ in tumor-infiltrating T cells.

Protective T cell responses against tumors require the production of Interferon gamma (IFN-γ). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-γ and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products.

Costimulation through TLR2 Drives Polyfunctional CD8 T Cell Responses.

Optimal T cell activation requires Ag recognition through the TCR, engagement of costimulatory molecules, and cytokines. T cells can also directly recognize danger signals through the expression of TLRs. Whether TLR ligands have the capacity to provide costimulatory signals and enhance Ag-driven T cell activation is not well understood.

Circular RNA expression in human hematopoietic cells is widespread and cell-type specific.

Hematopoietic stem cells differentiate into a broad range of specialized blood cells. This process is tightly regulated and depends on transcription factors, micro-RNAs, and long non-coding RNAs. Recently, also circular RNA (circRNA) were found to regulate cellular processes.

Measuring T Cell Responses by Flow Cytometry-Based Fluorescence In Situ Hybridization.

T cells produce a wide variety of effector molecules in response to infections, such as cytokines, chemokines, granzymes, and perforins. Because different stimuli promote the production of specific effector molecules, T cell responses come in different flavors. In addition, single-cell analysis of protein production revealed that T cells respond heterogeneously to activation.

Visualizing the life of mRNA in T cells.

T cells release ample amounts of cytokines during infection. This property is critical to prevent pathogen spreading and persistence. Nevertheless, whereas rapid and ample cytokine production supports the clearance of pathogens, the production must be restricted in time and location to prevent detrimental effects of chronic inflammation and immunopathology.

Combined Single-Cell Measurement of Cytokine mRNA and Protein Identifies T Cells with Persistent Effector Function.

Effective T cell responses entail the coproduction of IFN-γ, TNF-α, and IL-2. Cytokine production is determined by transcriptional and posttranscriptional events. However, increased transcript levels do not always translate into protein production, and therefore simultaneous transcripts and protein measurement are essential for the appropriate analysis of T cell responses.