Virus-Specific CD8⁺Lymphocytes Share the Same Effector-Memory Phenotype but Exhibit Functional Differences in Acute Hepatitis B and C

Abstract

Hepatitis B and hepatitis C viruses (HBV and HCV) are both noncytopathic and can cause acute and chronic infections of the liver. Although they share tropism for the same organ, development of chronic hepatitis is much more frequent following HCV infection, suggesting different mechanisms of viral persistence. In this study, we show that circulating HBV-and HCV-specific tetramer-positive CD8 cells during the acute phase of hepatitis B and C belong almost entirely to an effector-memory subset (CCR7 ؊ CD45RA ؊ ). Despite this phenotypic similarity, HBV-and HCV-specific CD8 cells show striking functional differences. HBV-specific tetramer-positive CD8 cells express high perforin content ex vivo, expand vigorously, and display efficient cytotoxic activity and gamma interferon (IFN-␥) production upon peptide stimulation. A comparable degree of functional efficiency is maintained after the resolution of hepatitis B. In contrast, HCV-specific CD8 cells in the acute phase of hepatitis C express significantly lower levels of perforin molecules ex vivo and show depressed CD8 function in terms of proliferation, lytic activity, and IFN-␥ production, irrespective of the final outcome of the disease. This defect is transient, because HCV-specific CD8 cells can progressively improve their function in patients with self-limited hepatitis C, while the CD8 function remains persistently depressed in subjects with a chronic evolution.Cytotoxic T lymphocytes (CTL) play a central role in the control of virus infections (15). In infections by noncytopathic viruses, they contribute to both virus elimination and pathology, because elimination of intracellular virus is achieved by the destruction of infected cells and by a cytokine-mediated suppression of viral-gene expression within host cells (6, 11). Therefore, characterization of the functional features of virusspecific CTL at the early stages of infections with noncytopathic viruses, including hepatitis B virus (HBV) and hepatitis C virus (HCV) that are able to chronically persist in the infected host, can provide important insights into the pathogenesis of viral clearance and persistence (4, 7).The use of HLA class I tetramers together with phenotypic markers of activation, homing, and differentiation represents a powerful tool to analyze ex vivo virus-specific CD8 cells (1, 25). Four subsets of CD8 cells can be distinguished by staining them with antibodies to CCR7, a chemokine receptor involved in homing to secondary lymphoid organs and surface molecules associated with naive and memory T-cell subsets: naive CD45RA ϩ CCR7 ϩ T cells, CD45RA Ϫ CCR7 ϩ central memory T cells, CD45RA Ϫ CCR7 Ϫ effector-memory T cells, and CD45RA ϩ CCR7 Ϫ differentiated effector T cells (2, 12, 31). Perforin expression and gamma interferon (IFN-␥) secretion have been reported to be predominant functions of the more differentiated CCR7Ϫ subsets (2, 31). Using tetramer technology to quantify virus-specific CD8 cells, the frequency of tetramer-positive lymphocytes has been shown to be high during the acute...

Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection

“…Treg might be an important target in future therapies against cancer or chronic infectious diseases [24]. A functional impairment of CD8 + T cells has also been described in chronic viral infection effecting humans, like human immunodeficiency virus (HIV) and hepatitis C virus (HCV) [35][36][37][38][39][40][41]. In addition, in both HIV and HCV infection CD4 + Treg have been reported to suppress antiviral T cell responses [1,[42][43][44][45].…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…During HCV infection, type 1 cytokine secretion patterns have been described for T cells involved in resolving infection [39,40], with possible participation of NKmediated activities [42], while predominant type 2 production has been described in chronic viremic infection [36,37]. We therefore studied cytokine production by peripheral NK cells freshly isolated from chronically infected patients.…”

“…Spontaneous resolution of HCV infection has been linked to vigorous and multi-specific T cell responses, while attenuated CD4 + and CD8 + T cell responses have been observed during the chronic phase of viral persistence [3][4][5][6]. Failure to control HCV replication has also been associated with functional defects of virus-specific CD8 + cytotoxic T lymphocytes (CTL) [7][8][9][10] and, most recently, to the appearance of viral escape mutations in immunodominant CD8 + CTL epitopes associated with a lack of or relative defects in HCV-specific CD4 + T cell responses [11][12][13]. Adaptive immune defects during HCV infection are not limited to HCV-specific immune responses and may reflect the broader effects of HCV on the editing of T cell responses also on other antigen specificities [14].…”

Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms

“…Recent studies in humans and in the chimpanzee model indicate that the promptness of both T helper cell and CTL responses after HCV exposure seem to be criti- cal factors in determining the outcome of acute infection, i.e. recovery versus viral persistence [21][22][23][24][25][26][27][28][29][30][31]. Moreover, these data demonstrate that CTL, despite being considerably expanded and expressing a memory effector membrane phenotype (CCR7 -) [30,32,33], are functionally inadequate to fight HCV in a multitude of acutely infected people undergoing a state of long-lasting liver immunopathology [21][22][23][24][25][26][27][28][29][30][31].…”