Abstract
We reported previously that a proportion of natural CD25+ cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg) were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25+ cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of ∼46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25+ cells and conventional T cells. Expression profiles, including cell death, activation, proliferation and transcriptional regulation, suggest a survival advantage of HCV-responsive Treg over the other cell populations. Since no Treg-specific activation marker is known, we tested 97 NS3-derived peptides for their ability to elicit CD25 response (assuming it is a surrogate marker), accompanied by high resolution HLA typing of the patients. Some reactive peptides overlapped with previously described effector T cell epitopes. Our data offers new insights into HCV immune evasion and tolerance, and highlights the non-self specific nature of Treg during infection.
Highlights
Hepatitis C virus is a small positive sense single stranded RNA virus, which causes persistent infection that leads to cirrhosis, cancer and liver failure
It is accepted that effector T cells are critical for clearing infections, but their function can be suppressed by the somewhat elusive regulatory T cells
Our hypothesis, supported by new data, is that a proportion of the regulatory T cells are stimulated by the virus and that these cells are a stable cell population
Summary
Hepatitis C virus is a small positive sense single stranded RNA virus, which causes persistent infection that leads to cirrhosis, cancer and liver failure. In the acute phase of the infection, the host usually mounts strong CD4+ and CD8+ T cell responses, but this wanes in the few months during the transition to persistence (reviewed in reference [1]). The frequency of circulating CD4+CD25+ cells (the cell population in which Treg are predominantly contained [11]) in the blood of HCV carriers was higher than in healthy donors and individuals who had resolved the infection [7]. The percentage of CD4+CD25+ cells within the infected liver was much higher than in the peripheral blood [8]. One basic property of Treg is that, once activated via the T cell receptor (TCR), they suppress a wide range of immune responses in vitro and in vivo in a contact-dependent manner [11]. Sugimoto et al [13] initially showed that depletion of CD25+ cells enhanced the proliferation of the remaining
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