IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Abstract

Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A+ T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver.

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Similar enrichment of both tissue‐resident and circulating CD56 bright NK cells has been found in the spleen, bone marrow and tonsils. The liver is also enriched for NK cells, half of which have the CD56 bright phenotype 111. Liver‐resident NK cells have been described to be CD56 bright Eomes high , with high expression of CD69, CXCR6, CCR5,112, 113, 114 with Eomes high cells retained in the human liver without recirculation for up to 13 years 114.…”

“…In particular, they may make up to 30%–50% of all intrahepatic T‐cells, mediated by their expression of chemokine receptors such as CXCR6 and CCR6, which bind the chemokines CXCL16 and CCL20, respectively, that are constitutively expressed in the liver 11. Intrahepatic MAIT cells have been shown to be highly activated and express CD69, HLA‐DR and CD38, and are positioned around bile ducts within hepatic portal tracts 111, 118. Furthermore, as their name suggests, they are abundant within the gut, particularly in the jejunum and colon10, 119 through their expression of gut‐homing markers α 4 β 7 and CCR9,11, 13, 118 as well as the lungs 120…”

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

“…MAIT cells share some similarities with invariant natural killer T (iNKT) cells, which are implicated in many autoimmune conditions,18, 19 including expression of a semi‐invariant TCR, restriction by non‐classical MHC molecules, and expression of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF)20 although many differences exist, notably the nature of the ligands and the restriction molecule. Other significant features are the remarkable abundance of MAIT cells, which comprise approximately 5% of T cells in peripheral blood11, 17 and 20–40% of liver T cells in humans,15, 21 and their wide tissue distribution in blood, mucosal tissues, liver and joints 15, 19, 22, 23, 24, 25. A peculiarity of MAIT cell biology is that although MR1 expression is ubiquitous,3, 26 it is normally found only at very low levels on the cell surface 26, 27, 28.…”

“…Although some other previously reported species differences may have been artefacts of a specific transgenic murine model,17 other differences include a more limited expression of CD161 in mice17, 24 and, of relevance to this review, a difference in IL‐17 production. Interleukin‐17 is abundantly produced by both mouse and human MAIT cells in response to mitogen, but in humans IL‐17 is not produced in response to TCR triggering 17, 25, 33. In general each section of this review discusses human data from clinical studies first, before addressing murine data where relevant.…”

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections

“…These hepatic MAIT cells represent the majority of T cells expressing NK markers and are the dominant IL-17A + T cell subset in human liver sinusoids. Unlike circulating MAIT cells they are reported to express markers of T cell activation, however, like circulating MAIT cells they have the ability to produce Th1 cytokines and IL-17A [50].…”