Preferential loss of IL‐2–secreting CD4+ T helper cells in chronic HCV infection†

Semmo, Nasser; Day, Cheryl L.; Ward, Scott M.; Lucas, Michaela; Harcourt, Gillian; Loughry, Andrew; Klenerman, Paul

doi:10.1002/hep.20669

Cited by 172 publications

(167 citation statements)

References 49 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…This could possibly be due to the relatively mild disease that was observed in most of our cases, agreeing with reports from other authors (Woitas et al 1997, Falasca et al 2006. Indeed, it has been hypothesised that failure to secrete IL-2 might lead to a disruption of IFN-γ and proliferative capacity, contributing to the development of a persistent infection (Semmo et al 2005). Our findings agree with those of Gramenzi et al (2005), who reported that there was an inverse correlation between ALT levels and IL-2 expression when cytokine profiles of patients with chronic disease were compared with patients who had persistently normal serum ALT levels.…”

supporting

confidence: 90%

Tissue and serum immune response in chronic hepatitis C with mild histological lesions

R-Viso¹,

Duarte²,

Pagliari³

et al. 2010

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

show abstract

supporting

confidence: 90%

Tissue and serum immune response in chronic hepatitis C with mild histological lesions

R-Viso¹,

Duarte²,

Pagliari³

et al. 2010

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

show abstract

“…12,13,38 Moreover, a similar failure in IL-2 production was observed in patients with an established condition of long-lasting chronic infection. 39 In addition, rapid inactivation of antigen-specific CD4 cells with impairment of IL-2 or tumor necrosis factor ␣ production and concurrent exhaustion of the CD8 response has recently been observed in persistent viral infections. 40 Thus, early functional inactivation of CD4 cells and failure to produce effector cytokines in the acute phase of HCV infection may affect the generation of an efficient antiviral immune response.…”

Section: Discussionmentioning

confidence: 99%

Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

et al. 2006

View full text Add to dashboard Cite

A timely, efficient, and coordinated activation of both CD4 and CD8 T cell subsets following HCV infection is believed to be essential for HCV control. However, to what extent a failure of the individual T cell subsets can contribute to the high propensity of HCV to persist is still largely undefined. To address this issue, we analyzed the breadth, vigor, and quality of CD4 and CD8 responses simultaneously with panels of peptides covering the entire HCV sequence or containing the HLA-A2-binding motif, and with recombinant HCV proteins in 16 patients with acute HCV infection by tetramer staining, ELISPOT, and intracellular cytokine staining for interferon ␥, interleukin ( S pontaneous clearance of hepatitis C virus infection occurs in a small percentage of acutely infected patients and is associated with a vigorous cellular immune response of a broad specificity. [1][2][3][4][5][6][7][8][9] In contrast, chronic infection is characterized by less vigorous and narrowly focused CD4 and CD8 T cell responses. The mechanisms responsible for immune failure in patients who do not succeed in clearing the virus spontaneously are still unclear. Although there have been several reports of the hepatitis C virus (HCV)-specific cellular immune response during acute illness, a comprehensive study analyzing simultaneously the contribution of each T cell subsets to the mechanisms of clearance or persistence has never been performed. Most recent reports used wide panels of 10-to 15-mer HCV peptides that cannot distinguish the relative contribution of CD4 and CD8 cells to the overall antiviral T cell response. [5][6][7][8][9][10][11] Alternatively, a small number of preselected epitopes of known HLA restriction or whole recombinant HCV proteins were tested. [12][13][14][15][16][17][18] Moreover, only limited information is available about the ex vivo profile of cytokine production in the acute phase of infection, because ELISPOT and intracellular cytokine staining (ICS) analysis were based on the measure of interferon-␥ (IFN-␥) only. 12,19 In the present study, we used panels of genotypematched, overlapping peptides covering the entire HCV sequence to obtain a reliable representation of the overall T cell response to HCV, associated with control of infec-

show abstract

“…3B), in accord with previous reports. 9 Therefore, the downregulation of CD127 expression may contribute to the relative IL-2 deficiency in the acute phase of HCV infection 27 that has been implicated in the primary failure of CD4 ϩ T cell responses 28 and weak CTL responses. We found no difference in IFN-␥ production according to CD127 expression.…”

Section: Discussionmentioning

confidence: 99%

Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence

et al. 2006

View full text Add to dashboard Cite

Interleukin-7 (IL-7) is required for the establishment and maintenance of memory CD4 ؉ and CD8 ؉ T lymphocytes, and cells lacking IL-7R␣ (CD127) demonstrate impaired IL-2 secretion and have a short life-span. Chronic HCV is characterized by T cells that are functionally impaired and exhibit an immature phenotype. To investigate the potential role of IL-7/IL-7R␣ in the outcome of HCV infection, we used multiparameter flow cytometry to characterize patients with acute infection (n ‫؍‬ 24), long-term chronic infection (12) and normal subjects (13). HCV infection per se resulted in downregulation of CD127 on total CD4 ؉ and CD8 ؉ T lymphocytes as compared to normal controls. Total expression was lowest in those patients who subsequently developed persistence and intermediate in those patients with acute-resolving infection. This reduction affected both naïve and effector/memory T cells. CD127 correlated phenotypically with upregulation of chemokine receptors CCR7 and CXCR4, expression of the anti-apoptotic molecule B cell leukemia/lymphoma 2 (Bcl-2), and enhanced IL-2 production. In six HLA A2-positive patients, we longitudinally tracked tetramer responses to HCV and CMV epitopes; at baseline, reflecting the expression of CD127 on whole T cell populations, viral-specific CTLs in patients who became chronic demonstrated lower CD127. In conclusion, CD127 is a useful marker of functional CD4 ؉ and CD8 ؉ T cells and its expression correlates with virologic outcome of acute HCV. These data provide a mechanistic basis for the observation that CTLs generated in early infection rapidly decline as chronicity is established; CD127 expression should be considered in the design of novel immunotherapeutic approaches. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/ 0270-9139/suppmat/index.html).

show abstract

Preferential loss of IL‐2–secreting CD4+ T helper cells in chronic HCV infection†

Cited by 172 publications

References 49 publications

Tissue and serum immune response in chronic hepatitis C with mild histological lesions

Tissue and serum immune response in chronic hepatitis C with mild histological lesions

Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence

Contact Info

Product

Resources

About