Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection

Abstract

Persistent infection with hepatitis B virus (HBV) remains a major global health threat, currently aff ecting over 350 million individuals worldwide and causing more than 1 million deaths annually. Immune clearance is thought to be mediated primarily through a strong virus-specifi c CD8 T cell response ( 1 ); marked quantitative and qualitative defects in this response have been described in patients with chronic HBV infection (CHB) ( 2 -4 ). Patients with uncontrolled infection are distinguished from healthy HBV carriers by the presence of a large lymphocytic infi ltrate in their livers, containing a high proportion of non -antigen-specifi c CD8 T cells ( 3,5 ). Little is known about the characteristics of this generalized CD8 T cell population and its potential contribution to the failure of viral control and liver immunopathogenesis.In this study, we defi ne the functional profi le of non -HBV-specifi c CD8 T cells in patients with CHB, and investigate aberrant expression of the proximal TCR-associated signaling molecules CD3 and CD28 as putative mechanisms contributing to the defects seen.In other diseases of chronic infl ammation and high-load antigenic persistence analogous to the situation in CHB, selective defects in global CD8 function have been associated with downregulation of CD3 ± CD28. These include autoimmune disorders ( 6, 7 ), malignancy ( 8 ), and chronic viral ( 9, 10 ) and bacterial ( 11 ) The infl amed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large infl ux of non -virus-specifi c CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specifi city, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinfl ammatory cytokines interferon-␥ and tumor necrosis factor-␣ . This aberrant functional profi le was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3 , and could be corrected in vitro by transfection of CD3 or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the infl amed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinfl ammatory cytokine environment.

Multiple cytokine expression profiles reveal immune-based differences in occult hepatitis B genotype H-infected Mexican Nahua patients

“…TGF-β modulation in OHB-infected patients is consistent with TGF-β involvement in the progression of liver disease (Cheong et al 2006, Douglas et al 2010, Li et al 2010. A decreased ability to produce IL-2 in HBV-infected patients with higher viral loads (Das et al 2008) and the fact that high concentrations of IL-2 in the serum are related with an early and spontaneous seroconversion and disease resolution (Debnath et al 2005) support an essential role of IL-2, which we found to be important in OHB-infected patients. Thus, our data suggest that viral transcription repression that results in an HBsAg negative serologic test and undetectable levels of HBV DNA in the serum may be IL-2 modulated in OHB-, genotype-H-infected Nahua patients.…”

Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection

“…15,16 CTLA-4 mediated inhibition may depend on the fact that it shares ligands (B7-1 and B7-2) with CD28 but has higher avidity; when the supply of these ligands is limited, CTLA-4-mediated inhibitory signaling could override CD28-mediated positive costimulation. In CHB, the ability of CTLA-4 to outcompete CD28 may be favored not only by the increase in CTLA-4, but also by the reduced levels of CD28 on CD8 T cells 17 and by the scarcity of B7 ligands on hepatocytes and other intrahepatic cells with antigen-presenting capability. 18 We postulated that CTLA-4-mediated coinhibition may be one of the pathways that drives T cells encountering their antigen in the liver towards Bimdependent apoptosis.…”

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

“…As the proliferative potential of antigen-specific T cells is considered to be a key factor in maintaining or restoring effective antiviral immunity, 16,17,28 it was of special interest to simultaneously evaluate the functional profile and the proliferative potential of Nef-specific CD4 and CD8 T cells during the course of the study. Thawed PBMCs were stained with CFSE, incubated with peptide pools for 5 days and, after restimulation, samples were stained according to our standard protocol, with the exception that the fluorescein isothiocyanate-conjugated (FITC) CD154 antibody was omitted so as not to interfere with the detection of CFSE.…”