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The virome, increasingly recognized as a critical component of the mammalian microbiota, modulates host physiology. An antiviral treatment approach reveals that, via RIG-I signaling, the commensal virome is essential for the homeostasis of intestinal intraepithelial lymphocytes.
Acid sphingomyelinase deficiency, which prevents degradation of sphingomyelin (SM), causes lysosomal SM overload both in mice and in patients with Niemann–Pick disease A or B. Altered cellular SM homeostasis disrupts the development and function of natural killer T cells by obstructing the presentation of lipid agonists by CD1d molecules.
Fibroblastic reticular cells (FRCs) are dynamic regulators of lymphoid tissue structure. Turley and colleagues show FRCs also support activated T cells by producing IL-6, which confers an advantage to CD8+ T cell memory responses.
The impact of the commensal intestinal virome on health and immunity has been relatively little studied. Zhou and colleagues find that commensal viruses have an important function in maintaining intestinal intraepithelial lymphocytes, with implications for inflammatory bowel disease.
Niemann–Pick disease is characterized by the cellular accumulation of sphingomyelin. Blumberg and colleagues use both mouse models and materials from patients with Niemann–Pick disease to show that sphingomyelin accumulation inhibits CD1d-restricted NKT cell activation and development.
NK cells make an important contribution to the destruction of tumors. Wei and colleagues demonstrate that NK cells within the tumor microenvironment undergo mitochondrial fragmentation leading to impairment of their function and survival.
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.
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.
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.
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.
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.