Tissue-resident T cells in hepatitis B: A new target for cure?

More than 240 million people worldwide are chronically infected with the hepatitis B virus (HBV) and are at risk of developing liver cirrhosis and hepatocellular carcinoma. HBV is a small, circular DNA virus that forms a mini-chromosome as its transcriptional template within the nucleus of hepatocytes. Therefore, HBV replication can be suppressed but the virus cannot be eliminated by nucleoside analogue therapy. Host immune responses play a signifi cant role in the outcome of HBV infection (Park and Rehermann, 2014). The majority of patients who acquire HBV infection during adulthood recover spontaneously with vigorous T cell and antibody responses that provide long-term control of small traces of persisting virus. In contrast, almost all patients who are infected at birth develop chronic infection. In chronic HBV infection, HBV-specifi c immune responses are profoundly impaired via multiple mechanisms, including the antigen-dependent induction of inhibitory molecules such as PD-1, Tim-3, and CTLA-4 (Boni et al., 2007; Rehermann, 2013). This results in an “exhausted” phenotype of antigen-specifi c T cells, similar to that observed in HIV infection and cancer. Even though a small percentage of patients recover spontaneously from chronic HBV infection, all eff orts to restore immune responses in patients with chronic HBV infection have failed. A partial recovery of HBV-specifi c T cell function has been achieved in vitro by stimulation with viral peptides in the presence of antibodies against inhibitory receptors (Fisicaro et al., 2010). However, it is not known whether the same can be achieved in vivo and whether these cells would maintain their functionality in the immunotolerant environment of the liver. In this issue, Pallett et al. describe a distinct population of tissue-resident memory T (TRM) cells that are enriched in the liver of patients with chronic HBV infection as compared with uninfected controls. TRM cells were identifi ed by their surface expression of CD69, which negatively regulates sphingosine-1-phosphate receptor 1 (S1P1)– mediated egress of T cells from tissues (Skon et al., 2013; Mackay et al., 2015). TRM cells lack expression of lymph node–homing molecules CD62L and CCR7. In their study, Pallett et al. (2017) distinguish between CD69+CD103− and CD69CD103 TRM cells based on the expression of the αEβ7 integrin (CD103), which binds to e-cadherin on epithelial cells. CD69 and CD103 have also been described as key markers for TRM cells in several other tissues, including skin, lung, and intestine (Mackay et al., 2013; Mueller and Mackay, 2016). In the liver, CD69+CD103− cells comprise a heterogenous population of memory T cells that includes unconventional T cells such as mucosal associated invariant T (MAIT) cells and γδ-T cells, some of which are also present in the peripheral blood. In contrast, CD69CD103 TRM cells are absent in the blood and account for ∼20% of memory CD8 T cells in the liver of patients with chronic HBV infection (∼10% in uninfected controls). Using t-distributed stochastic neighbor embedding (tSNE) multidimensional analysis, Pallett et al. (2017) demonstrate that CD69CD103 TRM cells express a uniqe transcriptional signature (T-betEomesBlimp-1Hobit). They also express specifi c chemokine receptors such as CXCR6 and CXCR3. Thus, CXCL16, released by activated myeloid cells, may mediate the migration of CXCR6 TRM to the site of infl ammation. Similar to other liver-resident cells such as Kupff er cells, TRM cells are localized in the vascular space of the liver sinusoids, from where they interact with hepatocytes through the fenestrated liver sinusoidal epithelial cell (LSEC) layer. In this location, TRM cells are exposed to the inhibitor molecule PD-L1, which is up-regulated on hepatocytes and LSECs in viral hepatitis (Mühlbauer et al., 2006). This is important because TRM cells express high levels of the exhaustion markers PD-1 and CD39. PD-1– PD-L1 interaction has been reported as the main mechanism that “turns off ” the antiviral cytokine production of highly functional HBV-specifi c memory T cells injected into HBV transgenic mice (Isogawa et al., 2005). Using both MHC multimer staining and stimulation with HBV-specifi c peptides, Pallett et al. (2017) show that ∼90% of HBV-specifi c T cells in the liver of patients with chronic HBV infection have a TRM phenotype (either CD69+CD103− or CD69CD103 cells). Despite high expression of PD-1 and CD39, they readily produce IFNγ, TNFα, and IL-2 upon