Gamma Delta T-lymphocytes in Hepatitis C and Chronic Liver Disease

Abstract

Discovered 30 years ago, gamma delta (γδ) T-lymphocytes remain an intriguing and enigmatic T-cell subset. Although in humans they comprise a small fraction of the total circulating T-lymphocyte pool, they represent an important T-cell subset in tissues such as the liver, with roles bridging the innate and adaptive immune systems. The associations of γδ T-lymphocytes with chronic liver disease have been explored – however, there remain conflicting data as to whether these T-cells are pathogenic or protective. In patients with some forms of liver disease, their expansion in the periphery and especially in the liver may indeed help pathogen clearance, while in other conditions their presence may, in contrast, contribute to disease progression. γδ T-cells can also express CD161, a C-type lectin, and such cells have been found to be involved in the pathogenesis of inflammatory disease. CD161+ T-cells of diverse subsets are known to be enriched in the livers of patients with chronic hepatitis C. This article serves to provide a review of the γδ T-cell population and its role in hepatitis C and other chronic liver diseases, and also explores a potential role of the CD161+ γδ T-cells in liver diseases.

MAIT cells: new guardians of the liver

“…Thus, the liver functions as a second 'firewall', clearing commensals from the portal circulation where intestinal defenses are overwhelmed, 1 and is enriched with a number of innate immune cells, including Kupffer cells (liver‐resident macrophages), natural killer (NK) cells and innate‐like T cells. In the human liver, mucosal‐associated invariant T cells (MAIT) cells are the most dominant population of innate‐like T cells, comprising up to 50% of all T cells in the liver, 2 which is in contrast to invariant NKT cells (iNKT; ~1%) and γδ T cells (~15%) 3 , 4 …”

“…In the human liver, mucosalassociated invariant T cells (MAIT) cells are the most dominant population of innate-like T cells, comprising up to 50% of all T cells in the liver, 2 which is in contrast to invariant NKT cells (iNKT;~1%) and γδ T cells (~15%). 3,4 The invariant T-cell receptor (TCR) rearrangement of MAIT cells, Vα7.2-Jα33, was first identified during an extensive analysis of the TCR repertoire of human CD4 − CD8 − (double-negative; DN) T cells, Porcelli et al 5 and subsequently shown to be characteristic of a novel population restricted by the non-polymorphic and highly evolutionarily conserved major histocompatibility complex (MHC) class Ib molecule, MHC class I-related protein 1 (MR1). 6,7 The relative abundance of Vα7.2-Jα33 transcripts in human gut biopsies, as well as the enrichment of homologous Vα19-Jα33 transcripts among murine lamina propria lymphocytes compared with intraepithelial lymphocytes or mesenteric lymph nodes, 7 led to this population being called MAIT cells.…”

Human gamma delta T cells: Evolution and ligand recognition

“…They are the major subset of γδ T cells in human blood and can comprise between 1–10% of total blood T cells in healthy humans [59]. These cells are also found at high frequency in the gut, liver and other mucosal tissues [60–63]. Vγ9Vδ2 T cells respond potently to certain tumor cells [64, 65] and to microbial pathogens such as Mycobacterium tuberculosis and leprae [66] and are thus a population of great interest for immunotherapeutic manipulation.…”

Expression of lectin-like transcript-1 in human tissues

“…The expression of CD161 has been widely studied. It has been described on the vast majority of NK cells 25 , on different innate-like T cell subset,s such as NKT cells 3 , mucosal-associated invariant T (MAIT) cells 26 , γδ T cells 27, 28 and in other T cell subgroups, both in the CD4+ and CD8+ compartments. CD161 defines cell populations with shared transcriptional and functional features across different human T cell lineages 8 .…”