Resident Memory T Cells and Their Role within the Liver

Abstract

Immunological memory is fundamental to maintain immunity against re-invading pathogens. It is the basis for prolonged protection induced by vaccines and can be mediated by humoral or cellular responses-the latter largely mediated by T cells. Memory T cells belong to different subsets with specialized functions and distributions within the body. They can be broadly separated into circulating memory cells, which pace the entire body through the lymphatics and blood, and tissue-resident memory T (T_RM) cells, which are constrained to peripheral tissues. Retained in the tissues where they form, T_RM cells provide a frontline defense against reinfection. Here, we review this population of cells with specific attention to the liver, where T_RM cells have been found to protect against infections, in particular those by Plasmodium species that cause malaria.

Keywords: liver; memory CD8+ T cells; resident memory T cells.

Figure 1

The liver is a unique niche for tissue resident memory cells. The portal vein delivers antigen-rich blood from the gastrointestinal tract and spleen to the liver. This blood flows through the liver hepatic sinusoids lined with a thin layer of fenestrated liver sinusoidal endothelial cell (LSEC). Liver T_RM cells are localized within the hepatic sinusoids, where they remain long-term and do not recirculate despite direct connection to the circulatory system and constant exposure to the blood. The expression of ICAM-1 and CXCL16 by LSEC can promote the retention of lymphocytes, through interactions with LFA-1 and CXCR6, respectively. Murine and human T_RM cells in the liver express CD69, CXCR6, CXCR3 and high levels of LFA-1. Of note, human but not murine T_RM cells express CD103. It has been suggested that this difference is associated with a broad versus a restricted expression of E-cadherin by human and murine hepatocytes, respectively. Intrahepatic lymphocytes including circulating and resident memory cells can access the surface of hepatocytes through LSEC fenestrae and exert effector functions. Using cytoplasmic protrusions, lymphocytes probe hepatocytes for the presence of antigen and can release factors such as GzmB and IFN-γ to promote hepatocyte killing. In murine studies, liver T_RM cells can be generated through different vaccination strategies to confer protection against Plasmodium parasites and in humans they have been associated with disease control against HBV and HCV.