Mathieu Mancini

Macrophages undergo extensive chromatin and metabolic remodeling to mount effective inflammatory responses. Here, we identify Interferon Regulatory Factor 1 (IRF1) as a pioneer factor that orchestrates these processes during IFNγ-driven macrophage activation. Integrative ATAC-seq, ChIP-seq, Hi-ChIP, and nascent RNA-seq demonstrated that IRF1 rapidly engages closed chromatin, initiates enhancer remodeling, and drives removal of repressive histone marks followed by deposition of activating modifications. IRF1-established enhancers form long-range chromatin interactions with target promoters, activating transcriptional programs that control immune effector functions, chromatin regulation, and cellular metabolism. Notably, IRF1 coordinates the IFNγ-induced metabolic switch from oxidative phosphorylation to aerobic glycolysis by transcriptionally regulating key metabolic enzymes, with metabolite profiles consistent with increased glycolysis and pentose phosphate pathway engagement, while remodeling the tricarboxylic acid (TCA) cycle to support immunometabolic outputs. IRF1-deficient macrophages fail to execute this coordinated metabolic reprogramming. High-density IRF1 motif arrays promote enhanced chromatin occupancy and recruitment of the BRG1-containing chromatin remodeling SWI/SNF complex. Pharmacologic inhibition of SWI/SNF ATPase activity (SMARCA2/4) disrupts IRF1-dependent chromatin remodeling and gene induction. Moreover, IRF1-induced enhancer states persist after IFNγ withdrawal, establishing durable epigenetic memory. Together, these findings establish IRF1 as a central integrator of chromatin remodeling, transcriptional control, and metabolic adaptation, linking pioneer-factor activity to macrophage plasticity and innate immune memory.

In the lower respiratory tract, the alveolar spaces are divided from the bloodstream and the external environment by only a few microns of interstitial tissue. Alveolar macrophages (AMs) defend this delicate mucosal surface from invading infections by regularly patrolling the site. AMs have three behavior modalities to achieve this goal: extending cell protrusions to probe and sample surrounding areas, squeezing the whole cell body between alveoli, and patrolling by moving the cell body around each alveolus. In this study, we found Rho GTPase, cell division control protein 42 (CDC42) expression significantly decreased after berry-flavored e-cigarette (e-cig) exposure. This shifted AM behavior from squeezing to probing. Changes in AM behavior led to a reduction in the clearance of inhaled bacteria, Pseudomonas aeruginosa . These findings shed light on pathways involved in AM migration and highlight the harmful impact of e-cig vaping on AM function.

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5–61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple’s disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4−CD8− T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4−CD8− αβ T cells exhibit intact responses to HLA class II–restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.