ZFP318 fuels memory B cells for success.

Diversity is a key feature of B cell biology-from BCR rearrangement to the heterogeneity of memory B cells. In this issue of Immunity, Wang et al. show that the zinc-finger protein ZFP318 supports mitochondrial health in certain memory B cells, thereby facilitating potent recall upon rechallenge.

Zfp36l1 establishes the high-affinity CD8 T-cell response by directly linking TCR affinity to cytokine sensing.

How individual T cells compete for and respond to IL-2 at the molecular level, and, as a consequence, how this shapes population dynamics and the selection of high-affinity clones is still poorly understood. Here we describe how the RNA binding protein ZFP36L1, acts as a sensor of TCR affinity to promote clonal expansion of high-affinity CD8 T cells. As part of an incoherent feed-forward loop, ZFP36L1 has a nonredundant role in suppressing multiple negative regulators of cytokine signaling and mediating a selection mechanism based on competition for IL-2.

An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells.

During B cell maturation, transitional and mature B cells acquire cell-intrinsic features that determine their ability to exit quiescence and mount effective immune responses. Here we use label-free proteomics to quantify the proteome of B cell subsets from the mouse spleen and map the differential expression of environmental sensing, transcription, and translation initiation factors that define cellular identity and function. Cross-examination of the full-length transcriptome and proteome identifies mRNAs related to B cell activation and antibody secretion that are not accompanied by detection of the encoded proteins.

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.

The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins.

CD8 T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that establish the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naïve CD8 T cells and the potency of the resulting cytotoxic lymphocytes.

A functional screen of RNA binding proteins identifies genes that promote or limit the accumulation of CD138+ plasma cells.

To identify roles of RNA binding proteins (RBPs) in the differentiation or survival of antibody secreting plasma cells we performed a CRISPR/Cas9 knockout screen of 1213 mouse RBPs for their ability to affect proliferation and/or survival, and the abundance of differentiated CD138 + cells in vitro. We validated the binding partners CSDE1 and STRAP as well as the mA binding protein YTHDF2 as promoting the accumulation of CD138 + cells in vitro. We validated the EIF3 subunits EIF3K and EIF3L and components of the CCR4-NOT complex as inhibitors of CD138 + cell accumulation in vitro.

Dynamic Post-Transcriptional Events Governing CD8 T Cell Homeostasis and Effector Function.

Effective T cell responses against infections and tumors require a swift and ample production of cytokines, chemokines, and cytotoxic molecules. The production of these effector molecules relies on rapid changes of gene expression, determined by cell-intrinsic signals and environmental cues. Here, we review our current understanding of gene-specific regulatory networks that define the magnitude and timing of cytokine production in CD8 T cells.

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.

Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells.

Memory T cells are critical for the immune response to recurring infections. Their instantaneous reactivity to pathogens is empowered by the persistent expression of cytokine-encoding mRNAs. How the translation of proteins from pre-formed cytokine-encoding mRNAs is prevented in the absence of infection has remained unclear.

Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8 T cells.

Effective T cell responses against invading pathogens require the concerted production of three key cytokines: TNF-α, IFN-γ, and IL-2. The cytokines functionally synergize, but their production kinetics widely differ. How the differential timing of expression is regulated remains, however, poorly understood.

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.

GATA1-Deficient Dendritic Cells Display Impaired CCL21-Dependent Migration toward Lymph Nodes Due to Reduced Levels of Polysialic Acid.

Dendritic cells (DCs) play a pivotal role in the regulation of the immune response. DC development and activation is finely orchestrated through transcriptional programs. GATA1 transcription factor is required for murine DC development, and data suggest that it might be involved in the fine-tuning of the life span and function of activated DCs.

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis.

CD8(+) T cells can respond to unrelated infections in an Ag-independent manner. This rapid innate-like immune response allows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, we show that murine CD8(+) T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γ but not of TNF-α and IL-2.

T-cells require post-transcriptional regulation for accurate immune responses.

Cytotoxic T-cells are crucial to protect us from intracellular pathogens and malignant cells. When T-cells become activated, they rapidly secrete cytokines, chemokines and cytotoxic granules that are critical to clear infected cells. However, when not properly regulated, these toxic effector molecules become one of the key mediators of autoimmune diseases.

Better safe than sorry: TOB1 employs multiple parallel regulatory pathways to keep Th17 cells quiet.

Th17 cells are key players in antibacterial and antifungal immunity, but have also been implicated in autoimmunity. Interestingly, Th17 cells poorly proliferate upon stimulation, a phenotype that was attributed to a decreased sensitivity to T-cell receptor (TCR) stimulation, and to low IL-2 production by Th17 cells. In this issue of the European Journal of Immunology, Santarlasci et al.

Helicobacter pylori Hp(2-20) promotes migration and proliferation of gastric epithelial cells by interacting with formyl peptide receptors in vitro and accelerates gastric mucosal healing in vivo.

Helicobacter pylori-derived peptide RpL1 aa 2-20 (Hp(2-20)) in addition to its antimicrobial action exerts several immunomodulatory effects in eukaryotic cells by interacting with formyl peptide receptors (FPRs). It has recently been shown that activation of FPRs facilitates intestinal epithelial cell restitution. We investigated whether Hp(2-20) induces healing of injured gastric mucosa and assessed the mechanisms underlying any such effect.