Dendritic Cells and T Cell Subsets in the Development of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with steatosis, inflammation and fibrosis. Liver dendritic cells (DCs) are usually tolerogenic in the sinusoidal milleu composed of immunosuppressive cytokines. In NAFLD and NASH, DCs become pro-inflammatory and modulate hepatic immune response. Murine liver DCs are three major subtypes: classical (lymphoid) cDC1 or the crosspresenters (CD8α+CD103+), classical (myeloid) cDC2 (CD11b+) and plasmacytoid pDCs (PDCA-1+Siglec-H+) and two additional subtypes or lymphoid + myeloid DCs and NKDCs. Similarly, human liver DCs are three subtypes or CD141+CLEC9A+, CD1c+ (BDCA1+) and pDCs (CD303+BDCA2+). Compared to blood human hepatic DCs are less immature and predominantly induce regulatory T cells (Tregs) and IL-4 secreting T cells (Th2). DCs polarize T cells into different Th types that are in interrelations in NAFLD/NASH. T helper 1 (Th1) (T-bet) cells are associated with adipose tissue inflammation. The differentiation of Th2 (GATA3) cells is induced by IL-4 DCs, increased in NAFLD. Similarly, Th17 cells (RORγt/ RORc) are increased in NAFLD and NASH. Tregs (FoxP3) are increased in the liver in steatosis and Th22 cells (AHR) are elevated in diabetes mellitus 2 (DM2) and adiposity. CD8+ T cells γδT cells and MAIT cells also contribute to liver inflammation.