The human liver contains specialized subsets of mononuclear phagocytes (MNPs) and T cells, but whether these have definitive features of tissue residence (long-term retention, lack of egress) and/or can be replenished from the circulation remains unclear. Here we addressed these questions using HLA-mismatched liver allografts to discriminate the liver-resident (donor) from the infiltrating (recipient) immune composition. Allografts were rapidly infiltrated by recipient leukocytes, which recapitulated the liver myeloid and lymphoid composition, and underwent partial reprogramming with acquisition of CD68/CD206 on MNPs and CD69/CD103 on T cells. The small residual pool of donor cells persisting in allografts for over a decade contained CX3CR1^hi/CD163^hi/CD206^hi Kupffer cells (KCs) and CXCR3^hi tissue-resident memory T cells (T_RM). CD8⁺ T_RM were found in the local lymph nodes but were not detected egressing into the hepatic vein. Our findings inform organ transplantation and hepatic immunotherapy, revealing remarkably long-lived populations of KCs and T_RM in human liver, which can be additionally supplemented by their circulating counterparts.

A significant proportion of patients infected with SARS‐CoV‐2 develop severe respiratory symptoms due to an excessive immune response. Treatment of this condition may include immunosuppressive therapies, such as IL‐6 receptor antagonists and corticosteroids, which pose a risk for patients with active or past hepatitis B virus (HBV) infection. In this prospective cohort study, we analysed the risk of HBV reactivation in patients with severe COVID‐19 and resolved HBV infection undergoing immunosuppressive therapy. From 15th March to 30th April 2020, 600 patients with severe COVID‐19 were admitted to our hospital and treated with immune modulators. Data regarding HBV infection were available in 484, of whom 69 (14%) were HBsAg negative/anti‐HBc positive. For these patients, HBV reactivation prophylaxis with entecavir was strongly recommended. Complete follow‐up was available in 61 patients: 72% were male, median age was 67 years, and anti‐HBs was >10 IU/mL in 72%. The immunosuppressive drug most used was tocilizumab (72%). Despite HBV prophylaxis recommendation, 38 (62%) patients received entecavir and 23 (38%) did not. Baseline features of both groups were similar. At follow‐up, we found no cases of HBsAg seroreversion and only 2 (3%) patients (no prophylaxis group) had detectable serum HBV‐DNA (<15 IU/mL). Both were anti‐HBs negative and had normal aminotransferase levels. Our data show that the risk of HBV reactivation in patients with severe COVID‐19 and resolved HBV infection undergoing immunosuppressive treatment is low. However, if a systematic follow‐up after hospital discharge is unfeasible in patients without anti‐HBs, a short course of antiviral prophylaxis may be a safe option.