The role of lipids in regulating macrophage antifungal immunity.

Macrophages are critical components of the antifungal immune response. Disturbance in the number or function of these innate immune cells can significantly increase susceptibility to invasive fungal infections. Pathogenic fungi cause billions of infections every year and have an unmet clinical need, with many infections associated with unacceptably high mortality rates that primarily affect vulnerable patients with underlying immune defects. Lipid metabolism has been increasingly appreciated to significantly influence macrophage function, particularly of macrophages residing in lipid-rich organs, such as the brain, or macrophages specialized at clearing dead cells including alveolar macrophages in the lungs. In this review, we provide an overview of macrophage lipid metabolism, and discuss how lipid recycling and dysregulation affect key macrophage functions relevant for antifungal immunity including phagocytosis, functional polarization, and inflammasome activation. We focus on the fungal pathogen Cryptococcus neoformans, as this is the most common cause of death from fungal infection in humans and because several lines of evidence have already linked lipid metabolism in the regulation of C. neoformans and macrophage interactions.

Nur77-Tempo mice reveal T cell steady state antigen recognition.

In lymphocytes, Nr4a gene expression is specifically regulated by antigen receptor signalling, making them ideal targets for use as distal T cell receptor (TCR) reporters. Nr4a3-Timer of cell kinetics and activity (Tocky) mice are a ground-breaking tool to report TCR-driven Nr4a3 expression using Fluorescent Timer protein (FT). FT undergoes a time-dependent shift in its emission spectrum following translation, allowing for the temporal reporting of transcriptional events. Our recent work suggested that Nr4a1/Nur77 may be a more sensitive gene to distal TCR signals compared to Nr4a3, so we, therefore, generated Nur77-Timer-rapidly-expressed-in-lymphocytes (Tempo) mice that express FT under the regulation of Nur77. We validated the ability of Nur77-Tempo mice to report TCR and B cell receptor signals and investigated the signals regulating Nur77-FT expression. We found that Nur77-FT was sensitive to low-strength TCR signals, and its brightness was graded in response to TCR signal strength. Nur77-FT detected positive selection signals in the thymus, and analysis of FT expression revealed that positive selection signals are often persistent in nature, with most thymic Treg expressing FT Blue. We found that active TCR signals in the spleen are low frequency, but CD69+ lymphoid T cells are enriched for FT Blue+ Red+ T cells, suggesting frequent TCR signalling. In non-lymphoid tissue, we saw a dissociation of FT protein from CD69 expression, indicating that tissue residency is not associated with tonic TCR signals. Nur77-Tempo mice, therefore, combine the temporal dynamics from the Tocky innovation with increased sensitivity of Nr4a1 to lower TCR signal strengths.