Intravascular immune surveillance against viremia requires spatiotemporal coordination between Kupffer cells and ILC1s.

Prompt sequestration and clearance of circulating virions by the liver are crucial for mitigating viral pathogenesis, yet the underlying immune mechanisms remain incompletely understood. Using real-time intravital imaging, here we reveal a tissue-specific behavioral adaptation of ILC1s that fortifies Kupffer cell (KC)-mediated intravascular immunosurveillance against viremia. At steady state, ILC1s constantly patrol and scan over KCs in liver sinusoids. Upon bloodstream infection with murine cytomegalovirus (MCMV) or vesicular stomatitis virus (VSV), KCs rapidly capture virions and trigger type I interferon production, which signals ILC1s to dock on infected KCs and undergo activation. Interferon-γ derived from arrested ILC1s facilitates viral clearance within KCs via an inducible nitric oxide synthase (iNOS)-NO-dependent mechanism. Impaired viral control in KCs, due to the absence of ILC1s, interferon-γ, or iNOS, leads to KC lysis and viral dissemination. Our study thus highlights a spatiotemporally coordinated defensive strategy between sessile and mobile tissue-resident immune sentinels in restraining viral infections.