TY - JOUR
T1 - On the impact of hepatitis C virus and heterologous immunity on alloimmune responses following liver transplantation
AU - Merritt, Elliot
AU - Londoño, Maria Carlota
AU - Childs, Kate
AU - Whitehouse, Gavin
AU - Kodela, Elisavet
AU - Sánchez-Fueyo, Alberto
AU - Martínez-Llordella, Marc
N1 - Funding Information:
The word was funded by the Roche Organ Transplantation Research Foundation (ROTRF), the Medical Research Council Centre for Transplantation (reference J006742/1), and the National Institute for Health Research Biomedical Research Centre based at Guy’s and St Thomas National Health Service Foundation Trust and King’s College London.
Funding Information:
The word was funded by the Roche Organ Transplantation Research Foundation (ROTRF), the Medical Research Council Centre for Transplantation (reference J006742/1), and the National Institute for Health Research Biomedical Research Centre based at Guy?s and St Thomas National Health Service Foundation Trust and King?s College London.
Publisher Copyright:
© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - alloantigen
KW - basic (laboratory) research/science
KW - cell death: exhaustion
KW - immune regulation
KW - immunosuppression/immune modulation
KW - infection and infectious agents – viral: hepatitis C
KW - infectious disease
KW - liver allograft function/dysfunction
KW - liver transplantation/hepatology
KW - translational research/science
UR - http://www.scopus.com/inward/record.url?scp=85087456194&partnerID=8YFLogxK
U2 - 10.1111/ajt.16134
DO - 10.1111/ajt.16134
M3 - Article
C2 - 32524678
AN - SCOPUS:85087456194
SN - 1600-6135
VL - 21
SP - 247
EP - 257
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 1
ER -
