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The PI3K pathway plays a key role in B cell activation and is important for the differentiation of Ab producing plasma cells (PCs). Although much is known about the molecular mechanisms that modulate PI3K signaling in B cells, the transcriptional regulation of PI3K expression is poorly understood. In this study, we identify the zinc finger protein Zbtb18 as a transcriptional repressor that directly binds enhancer/promoter regions of genes encoding class I PI3K regulatory subunits, subsequently limiting their expression, dampening PI3K signaling and suppressing PC responses. Following activation, dividing B cells progressively downregulated Zbtb18, allowing gradual amplification of PI3K signals and enhanced development of PCs. Human Zbtb18 displayed similar expression patterns and function in human B cells, acting to inhibit development of PCs. Furthermore, a number of Zbtb18 mutants identified in cancer patients showed loss of suppressor activity, which was also accompanied by impaired regulation of PI3K genes. Taken together, our study identifies Zbtb18 as a repressor of PC differentiation and reveals its previously unappreciated function as a transcription modulator of the PI3K signaling pathway. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 5 (IRF5) is a key signal-dependent transcription factor in myeloid cells. Its expression is induced by granulocyte-macrophage colony stimulating factor and interferon-gamma. IRF5 protein is further activated in response to stimulation, translocating to the nucleus where it mediates inflammatory responses. IRF5 is capable of both the up-regulation of pro-inflammatory genes and repressing anti-inflammatory mediators, thus polarising macrophages to a pro-inflammatory phenotype. We discuss IRF5 interactions with a wide range of transcriptional regulators that give rise to its diverse effects at the level of chromatin. [ABSTRACT FROM AUTHOR]

Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands. • Neutrophils have variable lifetimes in tissues • Neutrophils acquire distinct phenotypic and functional properties in tissues • Tissue-derived signals drive rapid adaptation of neutrophils • Neutrophil reprogramming in the lungs occurs in CXCL12+ niches. Neutrophils demonstrate plasticity in form and function depending upon the tissue types. [ABSTRACT FROM AUTHOR]