Volume 24 Issue 3, March 2023

A new study by Zhou et al. identifies a unique microglia state in Nasu-Hakola disease and new potential therapeutic targets.

A serendipitous behavioral observation in a mouse line led to the discovery that macrophages modulate acute pain. The macrophage-derived protein SNX25 sets the threshold for acute pain through tonic NGF signaling to cutaneous sensory neurons.

Dendritic-cell-biased thymic seeding progenitors provide stromal support for early T cell development through the expression of membrane-bound TNF.

Research shows that Vδ1 and Vδ3 γδ T cells that express PD-1 and display potent cytotoxic functions are key immune responders in HLA-class-I-negative colon cancers subjected to immune checkpoint blockade therapy.

Intrathymic dendritic cell (DC)-biased precursors act as hematopoietic stromal cells that support the generation of human T cell progenitors from hematopoietic progenitor cells, via crosstalk with immature thymocytes that express TNF receptor 2. This function of DC precursors can be exploited to generate T cell precursors and competent T cells for cell therapy.

The cholesterol metabolite receptor GPR183 regulates the secretion of IgA by intestinal plasma cells. This process requires epithelial cell sensing of commensal bacteria and the uptake of dietary cholesterol to generate the GPR183 ligand 7α,25-hydroxycholesterol. Upon GPR183 activation, IgA⁺ plasma cells remain at the center of intestinal villi and reduce their antibody secretion.

Prinz and colleagues discuss myeloid cell heterogeneity in the CNS and how cells are recruited and migrate into CNS niches.

Here, the authors show that IFNγ binding to heparan sulfate is a mechanism to restrain IFNγ at the site of production, thereby preventing high systemic levels of this cytokine and associated immunopathology.

Here, the authors show that acute influenza infection induces trained immunity in self-sustaining resident alveolar macrophages, which independently exert long-term antimetastatic immune surveillance in the lung via enhanced tumor killing.

Tanaka and colleagues show that an SNX25–Nrf2 pathway in dermal macrophages sets the threshold for pain sensitivity through modulating the production of the neurotrophic factor NGF.

Unlike metabolic reprogramming that is characteristic of macrophage inflammatory polarization responses to lipopolysaccharide and TLR4 stimulation, the metabolism underlying inflammatory responses to CD40 signaling is not well characterized. Here the authors show CD40 signaling drives fatty acid oxidation and glutamine metabolism resulting in regulation of the NAD⁺/NADH ratio, which in turn promotes antitumor and pro-inflammatory macrophage functions.

The formation of an immunological synapse is central to the ability of NK cells to lyse target cells. Here the authors show that Nogo receptor 1 (NgR1) might be a good target for cancer immunotherapy as it destabilizes the NK synapse, resulting in defective killing of tumor cells.

In humans, intrathymic development of DCs is evident but its physiological significance is unknown. Taghon et al. show intrathymic development of DCs as hematopoietic stromal support for the early stages of human T cell development via IRF8-driven transmembrane TNF.

Savage and colleagues identify a population of CD4⁺ T cells within the endogenous repertoire that exhibit hallmarks of overt self-reactivity, spontaneously adopt a follicular helper T cell phenotype and are enriched in non-lymphoid organs following sustained T_reg cell depletion.

Here the authors show that dihydroorotate dehydrogenase in the de novo pyrimidine synthesis pathway functions as a cell fate checkpoint that can be targeted to specifically diminish the number and function of effector T cells without affecting the memory T cell pool and response to infection.

Here the authors show how metabolic alteration of acyl chain composition affects phosphoinositide-driven signaling to initiate and sustain CD8⁺ T cell effector function during cell differentiation.

Reboldi and colleagues show that high-cholesterol diets influence IgA secretion. Cholesterol-derived metabolites act on plasma cell GPR183 receptors to alter cell positioning of IgA⁺ plasma cells within the lamina propria and suppress antibody responses to intestinal pathogens.

Colonna and colleagues report dysregulated gene expression in microglia harboring homozygous mutations of DAP12 from individuals with Nasu–Hakola disease, a form of early-onset dementia.