T Cells with a CD4⁺CD25⁺Regulatory Phenotype Suppress In Vitro Proliferation of Virus-Specific CD8⁺T Cells during Chronic Hepatitis C Virus Infection

Abstract

Chronic hepatitis C virus (HCV) infection is associated with impaired proliferative, cytokine, and cytotoxic effector functions of HCV-specific CD8؉ T cells that probably contribute significantly to viral persistence. Here, we investigated the potential role of T cells with a CD4؉ CD25 ؉ regulatory phenotype in suppressing virusspecific CD8؉ T-cell proliferation during chronic HCV infection. In vitro depletion studies and coculture experiments revealed that peptide specific proliferation as well as gamma interferon production of HCVspecific CD8؉ T cells were inhibited by CD4 ؉ CD25 ؉ T cells. This inhibition was dose dependent, required direct cell-cell contact, and was independent of interleukin-10 and transforming growth factor beta. Interestingly, the T-cell-mediated suppression in chronically HCV-infected patients was not restricted to HCV-specific CD8 ؉ T cells but also to influenza virus-specific CD8 ؉ T cells. Importantly, CD4 ؉ CD25 ؉ T cells from persons recovered from HCV infection and from healthy blood donors exhibited significantly less suppressor activity. Thus, the inhibition of virus-specific CD8 ؉ T-cell proliferation was enhanced in chronically HCV-infected patients. This was associated with a higher frequency of circulating CD4 ؉ CD25؉ cells observed in this patient group. Taken together, our results suggest that chronic HCV infection leads to the expansion of CD4 ؉ CD25 ؉

CD4+CD25hi regulatory T‐cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

“…46 Isolated Tregs from chronic HCV patients inhibited HCV specific CD8 1 T-cell responses but also peptide-specific CD8 1 CTL responses against other viruses. 40, 42 Here, we found no correlation between Treg frequencies and CTL, by comparing Treg frequencies between patients who had detectable HPV16 E6E7 specific CTL in the peripheral blood and patients who were negative for HPV16 E6E7 specific CTL. The lack of a correlation may be explained by the relatively small group of patients in which CTL were detectable.…”

“…Chronic HCV patients with a persistent infection had increased numbers of Tregs compared with controls who resolved their infections. 41,42 Also in these patients it is not yet clear whether the increased Treg frequencies are the cause or a consequence of chronic HCV infection.…”

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

“…In the chronic phase, T regulatory (CD4 + CD25 + ) cells suppress CD8 + cell responses, and thereby help the virus to persist. 48 It is important to calculate these ratios to observe the immunological status.…”

HIV-Specific IL-10-Positive CD8+ T Cells Suppress Cytolysis and IL-2 Production by CD8+ T Cells

“…PBMC were cultured with or without IL-10-positive cells in the same well or separated by a microporous membrane (0.4-m pore size; Costar, Corning) as previously described (29). Briefly, PBMC were placed into the lower chamber of a 24-well plate and the IL-10-positive cells were added into the same chamber or the upper chamber.…”