Liver Environment and HCV Replication Affect Human T-Cell Phenotype and Expression of Inhibitory Receptors

Abstract

Background & Aims There is an unclear relationship between T-cell expression of inhibitory receptors and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is not always the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver cells from patients with hepatitis C virus (HCV) and other viral infections. Methods We analyzed 36 liver samples from HCV antibody-positive patients (30 from patients with chronic HCV infection, 5 from patients with sustained virologic responses [SVRs] to treatment, and 1 from a patient with spontaneous clearance), with 19 paired blood samples, and 51 liver samples from HCV-negative patients, with 17 paired blood samples. Intrahepatic and circulating lymphocytes were extracted; T-cell markers and inhibitory receptors were quantified, for total and virus-specific T cells, by flow cytometry. Results Levels of the markers PD-1 and 2B4 (but not CD160, TIM3, or LAG3) were increased on intrahepatic T cells from healthy and diseased liver tissues, compared to T cells from blood. HCV-specific intrahepatic CD8+ T-cells from patients with chronic HCV infection were distinct in that they expressed TIM3 along with PD1 and 2B4. In comparison, HCV-specific CD8+ T cells from patients with SVRs and T cells that recognized cytomegalovirus (CMV) lacked TIM3, but expressed higher levels of LAG3; these cells also had different memory phenotypes and proliferative capacity. Conclusions T cells from liver express different inhibitory receptors than T cells from blood, independent of liver disease. HCV-specific and CMV-specific CD8+ T cells can be differentiated based on their expression of inhibitory receptors; these correlate with their memory phenotype and levels of proliferation and viral control.

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…We hypothesize that these differences are due to the unique tolerogenic properties of the liver environment, which induces expression of inhibitory receptors on hepatic T cells both in diseased and healthy conditions. 37 , 38 Furthermore, we found increased proportions of CD8 + CTL in LM-CRC and PM-CRC compared with primary CRC (Fig. 1A).…”

“…In addition, MMR-proficient LM-CRC are immunologically distinct from primary CRC in terms of immune infiltration. 35 Moreover, the unique immune environment in the liver 36 favors immunological tolerance, 36 and one of the mechanisms used by the liver to resist immune responses is the induction of expression of inhibitory receptors on hepatic T cells 37 , 38 and their ligands on hepatocytes and other liver tissue cells. 39 Previously we have observed that intra-tumoral CD8 + cytotoxic T cells (CTL) and CD4 + T helper cells (Th) are functionally compromised in LM-CRC, 40 and we also demonstrated that the suppression mediated by intra-tumoral regulatory T cells (Treg) in LM-CRC can be alleviated by blocking the inhibitory receptor CTLA4 and activating the stimulatory receptor GITR.…”

Immune responses and immunopathology in acute and chronic viral hepatitis

“…117). Intrahepatic HCV-specific CD8 + T cells in patients with chronic HCV infection are characterized by the co-expression of multiple inhibitory receptors 112,118,119 . The in vitro blockade of the PD1-PDL1 pathway rescues the exhausted CD8 + T cells from patients with chronic infection and restores the effector functions of these cells 113,120 (FIG.…”

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…In cases with chronic HBV or HCV infection, CTL exhaustion could be induced by continuously high viral loads, exposure to immunosuppressive cytokines such as IL-10 or TGF-β, emergence of Tregs or malfunction of DCs. Expression of multiple immune checkpoint molecules, such as PD-1, CTLA-4, LAG-3, CD244 and TIM-3, is a hallmark of T-cell exhaustion [22,23]. Tbet is an important regulator of immune checkpoint molecule expression in chronic viral inflammation [24].…”