The Roles of Liver-Resident Lymphocytes in Liver Diseases

Abstract

Tissue-resident lymphocytes usually reside in barrier sites and are involved in innate and adaptive immunity. In recent years, many studies have shown that multiple types of lymphocytes are resident in the liver, including memory CD8⁺ T (T_RM) cells; "unconventional" T cells, such as invariant natural killer T (iNKT) cells, mucosal associated invariant T (MAIT) cells, and γδT cells; innate lymphoid cells (ILCs) such as natural killer (NK) cells and other ILCs. Although diverse types of tissue-resident lymphocytes share similar phenotypes, functional properties, and transcriptional regulation, the unique microenvironment of the liver can reshape their phenotypic and functional characteristics. Liver-resident lymphocytes serve as sentinels and perform immunosurveillance in response to infection and non-infectious insults, and are involved in the maintenance of liver homeostasis. Under the pathological conditions, distinct liver-resident lymphocytes exert protective or pathological effects in the process of various liver diseases. In this review, we highlight the unique properties of liver-resident lymphocytes, and discuss their functional characteristics in different liver diseases.

Keywords: immune-mediated disease; liver; liver disease; liver-resident lymphocytes; residency.

Figure 1

The pathological or protective roles of liver-resident lymphocytes in liver diseases. The liver contains multiple types of tissue-resident lymphocytes, including CD8⁺T_RM cells, NK cells, ILCs, γδT cells, and NKT cells. Liver-resident lymphocytes serve as the first line of defense in response to infection and non-infectious insults, and play roles in immunosurveillance, immune regulation, and the maintenance of liver homeostasis. Liver-resident lymphocytes generally exert protective or pathological effects via producing antimicrobial or homeostatic effector molecules, and by cooperating with other immune cells. They are involved in many kinds of liver diseases, such as metabolic liver diseases (e.g., ALD and NFALD), acute liver injury, liver fibrosis, viral hepatitis, and hepatic carcinoma (HCC). Modulation of liver-resident lymphocytes responses may represent promising therapeutic method to treat liver diseases.