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

Abstract

Background and Aims: 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.

Bone Marrow: The Central Immune System

“…Effects in the Liver: Hepatic Stellate Cells, MTCs, and Liver Fibrosis BM can exert a controlling effect on long-lasting CD8+ MTCs not only directly within its own niches but also indirectly, via other cells, in niches of the liver. The liver is endowed with the capability to effectuate long-lasting functional T cell memory [181]. The homeostasis of memory CD8+ T cells in niches from the BM is thought to be mediated by IL-15/Il-15R heterodimer (15HD)-expressing myeloid cells.…”

“…Such mice developed and maintained long-lasting systemic antigen-specific CD8+ MTCs that were efficacious against tumor growth and Listeria infection. The MTCs appeared uniquely in the form of clusters in a specialized structure, i.e., sinusoidal niches of the liver [181].…”

“…Liver regeneration -Adipose-derived stem cells in hepatobiliary diseases [195] 2022 -Reversion of activated to quiescent HeSCs by NDV [184] 2009 -Inhibition of liver fibrosis by mirRNA [183] 2014 -Sustainment of CD8+ T cell memory by IL-15+ HeSCs [181] 2022…”