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Regulatory T cells (Tregs) play an important role in controlling alloreactivity after solid organ transplantation, but they may also impair antiviral immunity. We hypothesized that the Treg frequency and the Treg phenotype are altered in hepatitis C virus (HCV)–infected recipients of liver transplantation (LT) with possible prognostic implications. Tregs from 141 individuals, including healthy individuals, LT recipients with or without persistent HCV infections, and nontransplant patients with chronic HCV, were studied. A comprehensive phenotypic analysis was performed with multicolor flow cytometry, which included standard Treg markers [CD4+, CD25hi, CD127–, and FoxP3+ in addition to HLA DR, CCR7, CD45RA, CD62L, CD49d, CD39, ICOS and LAP‐TGFβ stainings. Healthy individuals and LT patients displayed similar Treg frequencies and largely comparable Treg phenotypes, which were stable over time after transplantation. In contrast, Tregs with a CD45RA–CCR7– effector phenotype were enriched in LT recipients with chronic HCV versus HCV‐negative transplant patients. HCV infection, rather than LT, altered the expression of functional markers on Tregs. A principal component analysis revealed distinct Treg phenotypes in HCV‐infected LT recipients with rejection and patients with recurrent graft HCV. In conclusion, Treg phenotypes are altered in HCV‐infected LT patients. An investigation of Tregs may possibly help to distinguish recurrent HCV from graft rejection. Further functional studies are needed to define the role of Tregs in determining the balance between antiviral and allogenic immunity. Liver Transpl 21:381–395, 2015. © 2015 AASLD.

Hepatitis E virus (HEV) infection is usually self-limited but may lead to acute hepatitis and rarely to fulminant hepatic failure. Persistent HEV infections have recently been described in organ transplant recipients receiving immunosuppressive medications, suggesting that HEV is controlled by adaptive immune responses. However, only few studies have investigated HEV-specific T-cell responses and immune correlates for the failure to clear HEV infection have not been established so far. We investigated T-cell responses against HEV in 38 subjects including anti-HEV-positive (exposed, n = 9) and anti-HEV-negative (n = 10) healthy controls, 12 anti-HEV-positive but HEV RNA-negative organ transplant recipients, and seven transplant recipients with chronic hepatitis E. Proliferation as well as cytokine production of CD4+ and CD8+ T cells was studied after stimulation with overlapping peptides spanning all proteins encoded by HEV-open reading frame (ORF)2 and HEV-ORF3. We show that (1) strong and multispecific HEV-specific T-cell responses are present in exposed healthy controls, and to a lesser extent also in recovered patients after transplantation; (2) that these responses are absent in patients with chronic hepatitis E but become detectable after viral clearance; and (3) that HEV-specific T-cell responses can be restored in vitro by blocking the PD-1 or CTLA-4 pathways. However, a combination of PD-1 and CTLA-4 blockade had no synergistic effects. We conclude that chronic hepatitis E is associated with impaired HEV-specific T-cell responses and suggest that enhancing adaptive cellular immunity against HEV might prevent persistent HEV infections. (HEPATOLOGY 2012)