MAIT cells: new guardians of the liver

Abstract

The liver is an important immunological organ that remains sterile and tolerogenic in homeostasis, despite continual exposure to non-self food and microbial-derived products from the gut. However, where intestinal mucosal defenses are breached or in the presence of a systemic infection, the liver acts as a second 'firewall', because of its enrichment with innate effector cells able to rapidly respond to infections or tissue dysregulation. One of the largest populations of T cells within the human liver are mucosal-associated invariant T (MAIT) cells, a novel innate-like T-cell population that can recognize a highly conserved antigen derived from the microbial riboflavin synthesis pathway. MAIT cells are emerging as significant players in the human immune system, associated with an increasing number of clinical diseases of bacterial, viral, autoimmune and cancerous origin. As reviewed here, we are only beginning to investigate the potential role of this dominant T-cell subset in the liver, but the reactivity of MAIT cells to both inflammatory cytokines and riboflavin derivatives suggests that MAIT cells may have an important role in first line of defense as part of the liver firewall. As such, MAIT cells are promising targets for modulating the host defense and inflammation in both acute and chronic liver diseases.

Figure 1

Distribution of human and murine MAIT cells in tissues. The frequency of MAIT cells (defined either by MR1 tetramers or as CD161⁺⁺Vα7.2⁺ T cells) within T cells, as has been described in the indicated tissues of mice and humans. MAIT cells are enriched within peripheral organs including the liver and gut, whereas they are less enriched within lymphoid organs. However, MAIT cells are much more abundant in humans compared with common laboratory strains of mice.

Figure 2

The phenotype of human MAIT cells and their mechanisms of activation. Mature MAIT cells in peripheral blood express the chemokine receptors CCR2, CCR5, CCR6, CXCR6, the C-type lectin-like receptor CD161, the dipeptidase CD26 and a CD45RO⁺CCR7⁻ effector memory phenotype, with the majority of human MAIT cells expressing the CD8 coreceptor. MAIT cells also express the transcription factors RAR-related orphan receptor γt (RORγt), T-bet and promyelocytic leukemia zinc-finger (PLZF) at rest. During bacterial infection, derivatives of the riboflavin biosynthesis pathway are captured by MR1 and presented on the surface of antigen-presenting cells (APCs). Alternatively, viruses can also rapidly activate MAIT cells in an MR1-independent manner owing to the induction of IL-18, IL-12 and IFNα. Activated MAIT cells express IFNγ, TNFα, granzyme B, perforin and IL-17.

Figure 3

Proposed role of MAIT cells in the liver. (a) In the steady-state liver, MAIT cells home to the bile ducts within the portal tract through their expression of the chemokine receptors CXCR6 and CCR6 where they are located both adjacent to the biliary epithelium and within hepatic sinusoids. This allows them to protect against infection via the biliary tree and from the portal and systemic circulation via the portal vein and hepatic artery. (b) In the event of ascending biliary infection and following bacterial breech of the biliary epithelium, liver MAIT cells are recruited through their upregulation of CXCR3 and increased expression of chemokines (CCL20) and adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) in the liver. MAIT cells are activated by riboflavin metabolites presented by MR1 expressed on both professional (Kupffer cells) and non-professional (BECs) antigen-presenting cells. MR1-activated MAIT cells release CD40L, which induces the expression of Fas, as well as cytotoxic molecules Granzyme B and perforin, leading to apoptosis of BECs. MAIT cells also express the proinflammatory cytokines IFNγ and TNFα, which activates Kupffer cells, BECs, liver sinusoidal endothelial cells (LSECs) and dendritic cells (DCs), whereas IL-7 produced by inflamed hepatocytes also promote IL-17 production from MAIT cells, leading to further inflammation and activation of Kupffer cells, BECs and hepatic stellate cells (HSCs). MAIT cells also produce IFNγ in response to IL-12 and IL-18, secreted by sinusoidal Kupffer cells activated by TLR4 (bacterial LPS) and TLR8 (viral ssRNA) agonists, leading to viral and bacterial control DCs.