On the impact of hepatitis C virus and heterologous immunity on alloimmune responses following liver transplantation

Elliot Merritt, Maria Carlota Londoño, Kate Childs, Gavin Whitehouse, Elisavet Kodela, Alberto Sánchez-Fueyo, Marc Martínez-Llordella*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Virus-induced heterologous immunity is considered a barrier to transplantation tolerance. Yet, hepatitis C (HCV)-infected liver transplant (LT) patients occasionally achieve operational tolerance. We investigated the mechanisms through which HCV infection modulates donor-specific T cell responses following LT and the influence of HCV eradication. We generated T cell lines from HCV-infected LT and non-LT patients before and after HCV eradication and quantified alloreactive responses using cell lines expressing single-HLA class-I antigens in the presence/absence of PD-1/CTLA-4 blockade. HCV-specific CD8+ T cells cross-reacted with allogeneic class-I HLA molecules. HCV-positive LT recipients exhibited a higher proportion of CD8+ T cells coexpressing inhibitory receptors (PD-1/CTLA4) than HCV-negative LT, and their expression correlated with CXCL10 plasma levels. This resulted in decreased antidonor and third-party proliferative responses, which were significantly reversed by HCV eradication. PD-1/CTLA-4 blockade increased the proportion of HCV-specific CD8+ T cells reacting against donor only before viral clearance. In conclusion, HCV infection results in the generation of HCV-specific CD8+ T cells capable of reacting against allogeneic HLA molecules. Following LT, this results in a PD-1/CTLA4-dependent decrease in alloimmune responses. Our findings challenge the notion that heterologous immunity is necessarily detrimental in LT and provide an explanation for the association between HCV eradication and immune-mediated allograft damage.

Original languageEnglish
Pages (from-to)247-257
Number of pages11
JournalAmerican Journal of Transplantation
Issue number1
Publication statusPublished - Jan 2021


  • alloantigen
  • basic (laboratory) research/science
  • cell death: exhaustion
  • immune regulation
  • immunosuppression/immune modulation
  • infection and infectious agents – viral: hepatitis C
  • infectious disease
  • liver allograft function/dysfunction
  • liver transplantation/hepatology
  • translational research/science


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