Cemento de ionómero de vidrio

The majority of the immunology of the liver covered so far has focused on the non-lymphocytic liver-resident cells and their ability to detect pathogen and/or their role in immune tolerance. Some attention should be given to the populations of lymphocytes both resident and transiting through the liver. Lymphocytes can be found scattered throughout the parenchyma of the liver,

as well as in the portal tracts, with the average human liver containing in the order of 1010_cells

[91]. As already alluded to the composition of the total lymphocyte population of the liver is unusual.

Between 40-60% of the intraheptic pool of lymphocytes are NK cells, which is more than a three-fold enrichment compared to the periphery [117, 118]. NK cells respond to a wide-range

Chapter 1. Introduction

of cell-surface ligands expressed by damaged or infected cells, which ensures self-tolerance is maintained, whilst responding to infected or transformed cells. NK cells kill target cells via the formation of an immune synapse to mediate subsequent lysis by releasing cytotoxic gran- ules (containing perforin and granzyme). However, NK cell functionality is not just restricted to their capacity to ˝kill as the name might suggest. NK cells also produce and release the pro-inflammatory cytokines, such as IFNγ and TNFα [119, 120].

Also the ratio of CD4+ to CD8+ T cells is altered in the liver. Under homoeostatic condi- tions CD4+ T cells outnumber CD8+ T cells in the periphery by approximately two to one. In the liver this ratio is reversed, with CD8+ T cells outnumbering their CD4+ counterparts. These T cells all express the αβ-chain T cell receptor (TCR) and respond to antigen presented in the context of MHC molecules [91]. The liver also contains a large number of γδ T cells which again have altered frequencies in the intraheptaic environment; in the periphery these cells normally represent approximately 3% of total lymphocytes, but in the liver these cells can represent up to 15% [87]. These cells play a predominant role in the presentation of lipid antigen.

Several lines of evidence suggest that the recruitment of leukocytes into the liver during chronic viral infections is largely mediated by the ability of chemokines to attract leukocytes to specific sites in the liver. The large majority of T cells infiltrating into the chronically inflamed liver express high levels of the following chemokines: CXCR3, CXCR6, CCR1 and CCR5; a tissue- infiltrating phenotype [121, 122, 123, 124]. Induction of the pro-inflammatory cytokines IFNγ and TNFα up-regulates expression of the CXCR3-ligands, CXCL9 and CXCL10. These have specifically been shown to be up-regulated with increased expression of the receptor CXCR3 on both CD4+ and CD8+ T cells in the liver compared to peripheral T cells in chronic hepatitis [121]. Importantly, studies using blockade strategies of CXCL9 and CXCL10 in vivo resulted in reductions in the recruitment of mononuclear cells into the liver, particularly those subsets that are known to express CXCR3 [71].

The ligand CXCL16 has also been reported to be up-regulated on hepatocytes [123], and en- gagement of CXCR6-expressing T cells through this interaction is important for the retention and survival of effector cells in the inflamed liver. More recently a subset of CXCR6+ liver- infiltrating CD8+ T cells which co-express the C-type lectin, CD161, capable of producing IL-17 and IFNγ have been reported in chronic HCV infection. This phenotype characterised by in- creased CD161+ T cells has also been reported in acute HBV in a limited number of patients.

Notably this phenotype was absent from HIV- cytomegalovirus (CMV)- and influenza-specific T cells [125]. The interaction of CXCR6:CXCL16 has also been shown to be relevant in the process of hepatic homing of NK and NKT cells [126].

Immune regulation in the liver can also be controlled by myeloid-lineage populations beyond that of the resident KC. Recent evidence has demonstrated a role for inflammatory monocyte- derived CD11b+ aggregates, that have been termed ˝intrahepatic myeloid cell aggregates for T cell clonal expansion (iMATE). The authors have described these iMATE as structures that pro- vide a ˝cocoon-like anatomic framework that enables and promotes the proliferation of CD8+ T cells locally, in the apparent absence of local antigen [127]. The formation of such struc- tures to enhance antigen-specific T cell numbers may be critical in aiding the immune response against hepatotropic infections. While myeloid-cell populations/structures like iMATE could be considered beneficial to an anti-viral or anti-tumour immune response, different populations of immature myeloid cells have also been described in the liver. One such subset is the MDSC. MDSC exhibit a wide-range of immune-suppressive functions, that affect both the innate and adaptive immune systems. Full description and discussion of these cells occurs throughout the thesis and will therefore not be covered in detail here.

Finally the liver microenvironment itself, independent of any single cell subset is involved in driv- ing immune tolerance. In this case the milieu is characterised by a state of nutrient deprivation. This nutrient-poor environment is achieved by the presence of a number of enzymes, central to immune regulation and immunometabolism. Examples of such enzymes include tryptophan 2,3-deoxygenase (TDO, an enzyme involved in the metabolism of L-trytophan to N-formyl- kynurenine), complemented by the action of indoleamine 2,3-dioxygenase (IDO), which when combined give rise to the immunosuppressive molecule kynurenine. The presence of IDO has previously been shown to been a critical mediator in the maintenance of the process of materno- fetal tolerance [128], and in the context of chronic HCV infection, where IDO expression is increased in the liver of patients [129]. KC and liver-resident DC are potential sources of IDO especially under inflammatory conditions. Yan et al. [130] specifically demonstrated T cell inhi- bition (T cell proliferation and induction of T cell apoptosis) upon enhanced levels of kynurenine and reduced tryptophan in vitro.

Another key enzyme capable of driving nutrient deprivation is the constitutively expressed arginase I. This enzyme, capable of metabolising the conditionally essential amino acid L-

Chapter 1. Introduction

arginine, is constitutively expressed by hepatocytes. Extracellular arginase I when released

from hepatocytes upon damage can deplete L-arginine. Local nutrient deprivation can limit T cell functionality and proliferation [131, 66, 64], thus potentially preventing successful adaptive immunity required upon sensing pathogenic insult. It is also possible that this deprivation could limit immune-mediated damage arising from excessive immune activation in the liver. Interest- ingly hepatocytes, although potent sources of the enzyme arginase I when damaged, are not the only source. MDSC can also produce and store large amounts of the enzyme [132]. The concept of metabolic regulation by cells such as MDSC in the liver is an exciting area of research.