Liver-Resident Metabolic Reprogramming and Th2/1 Cell Accumulation Drive Anti-Helminth Immunity During H. bakeri InfectionRunning title: Liver metabolic-immune crosstalk in helminth infection

The liver plays a pivotal yet understudied role in anti-helminth immunity. Here, we reveal that during Heligmosomoides bakeri infection, the liver serves as a critical immunological site, accumulating Th2 and Th2/1 hybrid cells through CXCR3-mediated recruitment driven by IFN-gamma and the chemokines CXCL9/10/11. Unlike traditional lymphoid organs, the liver maintains these functional Th2 and Th2/1 cells throughout the chronic and memory phases of infection, exhibiting potent cytokine production and no signs of exhaustion. Transcriptomic analysis of liver tissues uncovered stage-specific metabolic reprogramming, with early H. bakeri infection (6 days p.i.) suppressing oxidative phosphorylation and acute infection (14 days p.i.) activating immune pathways (e.g., TNF, JAK-STAT). Notably, metabolic shifts were independent of T cell infiltration and were instead induced by parasite excretory-secretory products (HES) and alarmins, which disrupted mitochondrial ATP production. The liver's glucose-rich microenvironment supported T cell effector function, including IL-5 production linked to elevated serum IL-5 and bile IgA. Our findings redefine the liver as a dynamic regulator of anti-helminth immunity, integrating metabolic and immune responses to sustain long-term host defense. These insights open new avenues for targeting liver-specific pathways to enhance parasite clearance.