Volume 20 Issue 11, November 2019

Therapeutic innovations of potentially great clinical impact should embrace the overarching values of research accountability, data transparency and validation through the scientific peer-review process.

Quantitative mass spectrometry applied to T cell activation reveals key insights into signal-transduction pathways. These data identify selective alterations in the concentration of proteins in activated T cells and detail previously undescribed protein–protein interactions.

Chronic exposure to fungal antigen drives the development of two subsets of CD4⁺ T_RM cells, distinguished by high or low expression of the integrin CD103, with opposing roles in inflammation-induced lung fibrosis.

Cyclic dinucleotides (CDNs) are potent activators of the innate immune sensor STING. The identification of a CDN importer sheds new light on the regulation of extracellular CDNs.

A report sheds new light on the molecular mechanisms responsible for the discrimination of self versus non-self TCR ligands and reveals the crucial role of the kinetics of LAT tyrosine phosphorylation in this.

The mechano-sensitive membrane channel PIEZO1 coordinates immune defense in the lungs.

Checkpoint blockade has revolutionized cancer immunotherapy; however, this approach is effective in only a subset of cancers. In their Review, Vignali and colleagues discuss novel checkpoint targets and their biology and clinical potential.

Gaudenzio and colleagues show that house dust mite extracts directly activate TRPV1⁺ sensory neurons, which promote allergic skin inflammation by inducing the degranulation of mast cells through the release of the neuropeptide substance P and activation of MRGPRB2.

Marichal and colleagues show that lung neutrophils in mice exposed to three distinct pro-allergic conditions release neutrophil extracellular traps that potentiate allergen uptake by dendritic cells and type 2 allergic inflammation.

Zúñiga-Pflücker and colleagues show that Notch signaling is required before the thymic stages of T cell development to inhibit the myeloid lineage potential in thymus-seeding progenitors.

Tissue-resident memory T cells (T_RM cells) are important for the localized protection of specific body compartments. Nakayama and colleagues identify heterogeneity in lung T_RM cells, with one subset driving fibrosis and inflammation and another reining in pathology in response to fungal challenge.

TCR ligation activates the tyrosine kinase ZAP-70 to phosphorylate the adapter LAT, which then coordinates TCR proximal signaling cascades. Weiss and colleagues show LAT-Y132 is critical to TCR ligand discrimination, as its phosphorylation represents a rate-limiting step in T cell activation due to a conserved glycine residue at position 131.

CRISPR activation (CRISPRa) can target select genes and, rather than being used to delete them, can be used to activate their expression. Chen and colleagues use a CRISPRa-based approach to drive the expression of multiple endogenous genes in tumors and presentation of the antigens encoded, thus enhancing antitumor immune responses.

Peyer’s patches (PPs) are sites of antibody production in the gut mucosa. Carroll and colleagues show the mechanosensory channel protein Piezo1 is required for the homeostatic maintenance of PPs. Specific loss of Piezo1 in FRCs disrupt PP structure and function, resulting in reduction of fecal IgA production and gut immunity.

Immature B cells expressing self-reactive BCRs induce anergy programs to promote tolerance. Busslinger and colleagues show that the transcription factor Ikaros enforces anergy by inducing transcription of negative-feedback regulators of the BCR and TLR–MyD88 pathways.

Malissen and colleagues provide a quantitative systems-level analysis of 15 distinct signalosomes that form within minutes of TCR stimulation of primary CD4⁺ T cells.

Cantrell and colleagues perform a comparative quantitative mass spectrometric analysis of the proteomes of naïve and activated CD4⁺ and CD8⁺ T cells. Proteomes are dynamically regulated and mTORC1 inhibition leads to differential consequences depending on cell state.