Issues

Ross Levine: Focus on the critical questions

IL-6 reveals its true nature.

Adipose tissue multipotent stromal cells provide support for adipose tissue–resident ILC2s through contact-mediated proliferation and IL-33–mediated stress-induced activation.

We discuss how the response by pDCs to nucleic acid sensing, which has a key role in antiviral immunity, can become chronic and then be associated with autoimmunity but also with promoting chronic viral infections.

Spencer et al. report the first description of human IL-6R deficiency in two patients presenting with recurrent infections, atopy, elevated IgE, and abnormal acute-phase responses.

Rana et al. demonstrate that white adipose tissue-resident multipotent stromal cells (WAT-MSC) support IL-33– and LFA-1/ICAM-1–mediated proliferation and type-2 cytokine expression by ILC2. Inversely, ILC2-derived IL-4 and IL-13 promote WAT-MSC eotaxin production and eosinophil recruitment, further maintaining type-2 immune homeostasis.

The study of Vetters et al. identifies the ubiquitin-modifying enzyme A20 as a critical regulator of mTOR. Loss of A20 unleashes mTOR activity and induces NK cell death, underscoring the need for a tightly controlled mTOR pathway for proper NK cell homeostasis.

T helper 17 cells (Th17) are important for fighting mucosal infections and in the pathogenesis of autoimmune disease. This work identifies the activating transcription factor 7 interacting protein (ATF7ip) as an important factor controlling Th17 differentiation by inhibiting Il2 gene expression.

The authors report three unrelated children with inherited TLR3 deficiency, impaired TLR3-dependent, IFN-α/β– and/or -λ–mediated, pulmonary epithelial cell–intrinsic immunity to influenza A virus, and life-threatening influenza pneumonitis.

We describe two unrelated patients with inherited IFNAR1 deficiency who suffered from life-threatening infections following measles or yellow fever virus vaccination and were otherwise healthy.

Liechti et al. demonstrate severe B cell perturbations in HIV-1 infection beyond described effects on memory B cells. Naive and marginal zone B cells down-regulate CD21 and display chemokine receptor and activation marker signatures associated with inflammation and diminished response to stimulation.

Crosspriming of CD8⁺ T cells by dendritic cells is crucial for host response against cancer and intracellular microbial infections. Ou et al. demonstrates that palmitoyl-protein thioesterase PPT1 is a phagosomal pH rheostat enabling both viral resistance and efficient crosspriming in cDC1s.

Natural killer cells can kill infected and transformed cells via two different cell death mechanisms. Prager et al. show that NK cells quickly kill their first targets by releasing cytotoxic granules and only use the slower death receptor–mediated cytotoxicity for their final kill.

Clarke et al. interrogate human T_RM cells from cancer and nonmalignant tissue. These analyses highlight that PD-1 expression in tumor-infiltrating T_RM cells was positively correlated with features suggestive of active proliferation and superior functionality rather than dysfunction.

Mastio et al. describe monocytic precursors of granulocytes. These precursors are barely detectable in steady state conditions and are not consequential for differentiation of granulocytes. However, they accumulate in cancer and substantially contribute to PMN-MDSC expansion.

Itch is a catalytic ubiquitin ligase that prevents autoimmunity in humans and mice. Here, Moser et al. show that Itch negatively regulates B cell proliferation and metabolic fitness to limit antigen-driven B cell responses and antibody production after immunization.

Fujino et al. report that Axl expression by basal cells within the lung epithelium causes cell cycle reentry and symmetric division. Sustained Axl stimulation in the presence of apoptotic cells is implicated in epithelial hyperplasia in inflammatory lung disease.

Extracellular vesicle (EV)–cargo miRNAs mediate intercellular communications. How cells selectively sort the miRNAs into EVs remains unclear. Lee et al. demonstrate a novel mechanism by which functional miRNAs are selectively sorted into EVs via caveolin-1/hnRNPA2B1 complex. This process is regulated by stimulation-associated posttranslational modifications of both cav-1 and hnRNPA2B1.