New insights into iNKT cells and their roles in liver diseases

Abstract

Natural killer T cells (NKTs) are an important part of the immune system. Since their discovery in the 1990s, researchers have gained deeper insights into the physiology and functions of these cells in many liver diseases. NKT cells are divided into two subsets, type I and type II. Type I NKT cells are also named iNKT cells as they express a semi-invariant T cell-receptor (TCR) α chain. As part of the innate immune system, hepatic iNKT cells interact with hepatocytes, macrophages (Kupffer cells), T cells, and dendritic cells through direct cell-to-cell contact and cytokine secretion, bridging the innate and adaptive immune systems. A better understanding of hepatic iNKT cells is necessary for finding new methods of treating liver disease including autoimmune liver diseases, alcoholic liver diseases (ALDs), non-alcoholic fatty liver diseases (NAFLDs), and liver tumors. Here we summarize how iNKT cells are activated, how they interact with other cells, and how they function in the presence of liver disease.

Keywords: NKT cells; chemokine; cytokine; immune; liver diseases.

Figure 1

Activators of NKT cells. α-Galcer and some of its analogues (e.g.ThrCer, α-GalCer-diol, 6′-modifed α-GalCer analogues), iGb3, and LPS are among lipid antigens proven to activate NKT cells via the CD1d-dependent pathway; interleukins such as IL-2, IL-12, IL-15, IL-18, IL-21, and IL-33 promote NKT cells by binding directly to their interleukin receptors; CC/CXC/CX3C chemokines are associated with the recruitment and proliferation of NKT cells, with non-exclusive matches with their receptors that come in the form of GPCRs. Also, α-Galcer and some interleukins may also lead to activation-induced apoptosis of NKT cells. α-GalCer, α-galactosylceramide; ThrCer, threitolceramide; iGb3, isoglobotrihexosylceramide; LPS, lipopolysaccharide; IL, interleukin.

Figure 2

Interactions between NKT cells and hepatocytes, dendritic cells, Kupffer cells, and B cells. (A) Hepatocytes present lipid antigens to TCR on NKT cells via the CD1d-dependent pathway; hepatocytes release IL-7 to activate NKT cells; NKT cells secrete TNF-α that has dual functions on hepatocytes; NKT cells express FasL and induce Fas expression on hepatocytes, leading to apoptosis of hepatocytes. (B) NKT cells secrete IFN-γ to recruit T cells to kill hepatocytes. (C) B cells present lipid antigens to NKT cells through CD1d; NKT cells and B cells contact each other directly through CD40L/CD40 and CD28/CD80, 86; NKT cells secrete IL-21 and IFN-γ to promote B cells. (D) Kupffer cells present lipid antigens to TCR on NKT cells via the CD1d-dependent pathway; Kupffer cells express LFA-1 and SIRPα, which bind with ICAM-1 and CD47, respectively, on NKT cells to activate NKT cells; Kupffer cells secrete IL-12, IL-1β, IL-15, and AIM to recruit and promote NKT cells; NKT cells in return produce pro-inflammatory IL-4 and IFN-γ to function on Kupffer cells. Notably, over-stimulation of NKT cells by Kupffer cells leads to apoptosis of NKT cells. (E) Dendritic cells (especially myeloid dendritic cells, mDC) present lipid antigens via CD1d towards NKT cells to activate NKT cells; dendritic cells secrete IL-27 and IL-12 to activate NKT cells; NKT cells express CD40L to bind with CD40L and reciprocally benefit dendritic cells. mDC, myeloid dendritic cells; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; SIRP, signal regulatory protein; LFA, lymphocyte function-associated antigen; ICAM, intercellular adhesion molecule; AIM, apoptosis inhibitor expressed by macrophages.

Figure 3

NKT cells interact with CD8+ and CD4+ T cells through CD40/CD40L and secretion of IL-4 and IL-13. The main functions of NKT cells on CD4+ T cells are stimulatory, while on CD8+ T cells they are both stimulatory and inhibitory, as NKT cells can harass their chemotaxis. NKT cells potentiate Tregs by secreting IL-2, IL-10, and TGF-β; Tregs have a negative impact on CD8+ and CD4+ T cells as well as NKT cells. IL, interleukin; TGF, tumor growth factor; Treg, regulatory T cells.