Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocytes

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 CX3CR1hi/CD163hi/CD206hi Kupffer cells (KCs) and CXCR3hi tissue-resident memory T cells (TRM). CD8+ TRM 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 TRM in human liver, which can be additionally supplemented by their circulating counterparts.