CD8(+) T cell memory is sustained in mice by hepatic stellate cells

Long‐lasting immunological memory is the ultimate goal of vaccination. Homeostatic maintenance of memory CD8(+) cytotoxic T cells (MemCD8TCs) is thought to be mediated by IL‐15/IL‐15R heterodimer (15HD)‐expressing myeloid cells. Nonmyeloid hepatic stellate cells (HSCs) also express 15HD, but their role in maintaining MemCD8TC homeostasis is unknown. APPROACH AND RESULTS: We engineered a genetically engineered mouse in which IL‐15R complementary DNA (cDNA) had been inserted in‐frame with lecithin‐retinol acyltransferase gene and bred onto an IL‐15R‐KO (15R‐KO) genetic background (L15R) that expressed IL‐15R in HSCs at normal levels, but not in other liver cells. Outside of the liver of L15R mice, IL‐15R expression was found in a number of organs, but not in dendritic cells and macrophages. The low IL‐15R expression in the bone marrow (BM) of L15R mice was eliminated by the reconstitution of lethally‐irradiated L15R mice with 15R‐KO BM to generate L15RC mice. Because MemCD8TC maintenance is mediated by 15HD, not empty IL‐15R, 15HD content in L15R mice was determined and found for liver, lung, kidney, and heart. L15R and L15RC mice developed and maintained long‐lasting, systemic antigen‐specific MemCD8TCs that were efficacious against tumor growth and Listeria monocytogenes infection in an antigen‐specific manner. Among the four organs with 15HD content, liver‐associated MemCD8TCs were different from those found in the lung, kidney, and heart in two ways: (1) they were quantitatively the most numerous, and (2) they appeared uniquely in the form of clusters in a specialized structure, sinusoidal niches of the liver. CONCLUSIONS: The liver, the largest organ of the body, is endowed with the capability of effectuating long‐lasting functional cytotoxic T cell memory.