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Analysis of the relationship between cytokine secretion and proliferative capacity in hepatitis C virus infection
Author(s) -
Semmo N.,
Krashias G.,
Willberg C.,
Klenerman P.
Publication year - 2007
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/j.1365-2893.2007.00842.x
Subject(s) - elispot , immunology , hepatitis c virus , peripheral blood mononuclear cell , biology , cytokine , t cell , secretion , interferon , virology , flow cytometry , virus , immune system , in vitro , endocrinology , biochemistry
Summary. CD4 + T‐cell responses are important for the outcome of hepatitis C virus (HCV) infection. However, the functional status of HCV‐specific CD4 + T cells in persistent infection is poorly understood. It is generally recognized that proliferative capacity of HCV‐specific CD4 + T cells is weak or absent in persistent infection, but whether this results from deletion of antigen‐specific cells or represents maintenance of antigen‐specific but poorly proliferative populations is not defined. We used a set of ex vivo assays to evaluate the functionality of HCV specific CD4 + T cells in persistent and resolved infection. Peripheral blood mononuclear cells (PBMC) from 24 prospectively recruited HCV polymerase chain reaction (PCR) positive individuals, 12 spontaneously resolved individuals (i.e. anti‐HCV+, PCR−) and 11 healthy controls were analysed for interferon‐ γ (IFN‐ γ ) and interleukin 2 (IL‐2) secretion by enzyme linked immunospot assays (ELISpot). HCV‐specific CD4 + proliferative responses of carboxy fluorescein succinimidyl ester‐labelled PBMC were assessed using a sensitive single cell flow cytometric assay. Sustained IFN‐ γ ELISpot responses were observed in the PCR+ group. However, proliferation of HCV‐specific CD4 + T cells in the PCR+ group was substantially reduced on a per cell basis, in parallel to IL‐2 secretion, compared with responses in the PCR− group. In PCR− individuals, a strong relationship between cytokine secretion and proliferative capacity was seen. However, in PCR+ individuals, IFN‐ γ secretion far exceeded proliferative capacity. During persistent HCV infection, some CD4 + T‐cell specificities appear to be lost, as measured using a range of techniques, but others, potentially important, are maintained as IFN‐ γ secretors but with low proliferative capacity even using a highly sensitive assay. Such subsets may yet play a significant role in vivo and also provide a template for modulation in immunotherapeutic interventions.