Suppression of HCV-specific T cells without differential hierarchy demonstrated in persistent HCV infection

Abstract

Hepatitis C virus (HCV) has a high propensity for persistence. To better define the immunologic determinants of HCV clearance and persistence, we examined the circulating HCVspecific T-cell frequency, repertoire, and cytokine phenotype ex vivo in 24 HCV seropositive subjects (12 chronic, 12 recovered), using 361 overlapping peptides in 36 antigenic pools that span the entire HCV core, NS3-NS5. Consistent with T-cell-mediated control of HCV, the overall HCV-specific type-1 T-cell response was significantly greater in average frequency (0.24% vs. 0.04% circulating lymphocytes, P ‫؍‬ .001) and scope (14/36 vs. 4/36 pools, P ‫؍‬ .002) among the recovered than the chronic subjects, and the T-cell response correlated inversely with HCV titer among the chronic subjects (R ‫؍‬ ؊0.51, P ‫؍‬ .049). Although highly antigenic regions were identified throughout the HCV genome, there was no apparent difference in the overall HCV-specific T-cell repertoire or type-1/type-2 cytokine profile relative to outcome. Notably, HCV persistence was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequency of CD4 ؉ CD25 ؉ regulatory T cells (7.3% chronic vs. 2.5% recovered, P ‫؍‬ .002) that could directly suppress HCV-specific type-1 CD8 T cells ex vivo. In conclusion, we found that HCV persistence is associated with a global quantitative and functional suppression of HCV-specific T cells but not differential antigenic hierarchy or cytokine phenotype relative to HCV clearance. The high frequency of CD4 ؉ CD25 ؉ regulatory T cells and their suppression of HCV-specific CD8 T cells ex vivo suggests a novel role for regulatory T cells in HCV persistence.

Regulatory T cells and the liver: A new piece of the puzzle

“…26 As for CD25ϩ Tregs, HCV persistence was associated with in- creased circulating CD25ϩTregs that directly suppressed HCV-specific CD8 T cell IFN␥ response ex -vivo. 27 In this study by Sugimoto et al, HCV-specific CD8 T cell response was augmented by CD4-depletion in HCV-infected but not in HCV-recovered subjects, suggesting that CD4 T cells (presumably CD25ϩ Tregs) were suppressing HCV-specific CD8 T cells during chronic infection. Subsequently, increased frequency and suppressive function of CD25ϩ Tregs in HCV-infected patients was confirmed in a detailed study by Cabrera et al, further demonstrating Treg secretion of TGF␤ and IL10 and inhibition of Treg suppression by TGF␤1 blockade.…”

Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis

“…Tregs expand during HCV infection in humans and this has been suggested to be involved in the establishment of a persistent infection [7, 62, 63]. CD4 + CD25 + Tregs isolated from HCV-infected patients inhibit antiviral CD8 + T cell responses while depletion of CD4 + Tregs enhances proliferation of remaining T cells [64, 65]. Several studies have showed a correlation between increased CD4 + Treg numbers and chronic HCV infection [7, 64, 65].…”

“…CD4 + CD25 + Tregs isolated from HCV-infected patients inhibit antiviral CD8 + T cell responses while depletion of CD4 + Tregs enhances proliferation of remaining T cells [64, 65]. Several studies have showed a correlation between increased CD4 + Treg numbers and chronic HCV infection [7, 64, 65]. However, in these studies, it remained unclear if these correlations stemmed from an HCV-specific tolerogenic response or from a nonspecific response induced by inflammation.…”

HCV–HIV Coinfection: Simple Messages from a Complex Disease

“…Such cells, which are best tracked using the expression of transcription factor FOXP3, have been demonstrated in many chronic inflammatory states and infections, including HCV [24]. Regulatory T cells may be generated in the thymus (natural Tregs) or in the periphery, as a result of antigenic stimulation, and act to inhibit function of antigen-specific T cells, including HCV-specific CD8 + T cells [25,26].…”