Cutting edge: Identification of hepatitis C virus-specific CD8+ T cells restricted by donor HLA alleles following liver transplantation. Rosen HR, Hinrichs DJ, Leistikow RL, Callender G, Wertheimer AM, Nishimura MI, Lewinsohn DM. J Immunol 2004;173:5355–5359.
By necessity, human liver transplantation is performed across HLA barriers. As a result, intracellular infection of the allograft presents a unique immunologic challenge for the recipient's immune system. In this study, we describe the presence of HLA-A2-restricted, hepatitis C virus (HCV)-specific CD8+ T cells in liver transplant recipients in whom the allograft is HLA-A2 positive and the recipient is HLA-A2 negative. These memory-effector T cells are recipient derived and recognize HCV peptide uniquely in the context of HLA-A2. Furthermore, these cells were absent before the transplant, suggesting that the allograft is capable of selectively expanding naive CD8+ T cells. The in vitro specificity to donor HLA allele-restricted CD8+ T cells suggests that these cells may function to control HCV spread in the allograft. (J Immunol 2004;173:5355–5359.)
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CD8+ T cells are thought to play a critical role in hepatitis C virus (HCV) infection.1, 2 During acute HCV infection, HCV-specific CD8+ T-cell responses are typically vigorous, especially in persons who clear the virus spontaneously,3, 4 and their absence is associated with chronic viremia.5 Less clear is their function once chronic HCV infection has been established.6, 7 On one hand, HCV-specific cellular immunity could still be important by containing viral spread, despite not fully controlling the virus. On the other hand, it has been hypothesized that the ongoing attack on infected hepatocytes by HCV-specific CD8+ T cells might be a key component of the vicious circle of cell destruction and inflammation, ultimately leading to fibrosis, liver cirrhosis, and liver cancer.
In patients with chronic HCV infection who undergo liver transplantation, this equation becomes even more complicated. Infection of the allograft with HCV is almost inevitable, and the course of hepatitis C in the transplanted liver can be rather aggressive.8 This occurs in a host in whom immunosuppressive therapy directly affects the cellular immune response, including virus-specific CD8+ T cells. In addition, a unique immunological scenario plays out because liver transplantations are performed without specific matching of the donor and recipient human leukocyte antigen (HLA) alleles. As a consequence, HCV-infected cells, which are mainly, if not exclusively, contained in the donor liver,1 will present viral antigen via HLA alleles not normally expressed by the recipient. The consequences of this HLA mismatch between donor and recipient are not well understood but could have important implications for liver transplantation in HCV-infected patients. In addition, posttransplantation immunology has the potential to be an important human model that provides unique insights into HCV immunopathogenesis.
The report by Rosen et al. adds an important piece to this largely unsolved puzzle by demonstrating that new HCV-specific populations of virus-specific CD8+ T cells are expanded after liver transplantation, and that these cells are surprisingly restricted by donor HLA alleles yet derived from the recipient's original T-cell pool. The authors employed HLA class I tetramer-peptide complexes to directly visualize antigen-specific T cells on the single cell level using fluorescent flow cytometry. Class I tetramers are uniquely suited for this kind of study as they directly bind with high sensitivity and specificity to the T cell of interest,9 and they are independent of T-cell function, which might be compromised by immunosuppressive therapy. Using class I tetramers restricted by the donors' HLA class I allele A2, which was not expressed by the liver recipients, the authors screened the recipients' peripheral blood mononuclear cells at several time points after liver transplantation. Surprisingly they detected HLA-A2–restricted HCV-specific CD8+ T cells in 2 out of 4 individuals that were clearly derived from the recipients' pool of T cells. This was demonstrated by the fact that the T-cell clones did not express HLA-A2, which was expressed by the donors, but rather only HLA alleles expressed in the recipient. In addition, all the HCV-specific T cells expressed the Y chromosome in 1 of the 2 subjects who had received a liver from a female liver donor. Importantly, the authors also tested in more detail whether the T-cell clones could recognize the antigen exclusively when presented by HLA-A2, or whether they would also recognize the antigen when presented by the HLA alleles expressed in the recipients. Such cross-reactivity was not detected, further establishing the conclusion that the HCV-specific T cells were derived from the recipient but restricted by a donor HLA allele.
What are the clinical implications of these findings? The authors suggest these T-cell clones could be exploited for adoptive immunotherapy in liver transplant patients with severe recurrence of HCV infection in the allograft. This is certainly an intriguing idea given the often problematic course of HCV reinfection after transplantation.8 Before this is realized, certain issues need to be addressed. Most importantly, the effects of these HCV-specific CD8+ T cells on the allograft need to be established. One would hope that the new T-cell specificities, which could have not been present in the recipient before the transplantation of the new liver, would contribute additional pressure on the circulating HCV strain,10 thus potentially containing it more efficiently. However, as stated in the introduction, a correlation between HCV-specific CD8+ T cells and the clinical course of chronic hepatitis C has not been established. It should be noted that in the chimpanzee model, the virus escapes from virtually all HCV-specific CD8+ T cells present in the livers of animals with chronic infection.11 Despite chronic viremia, these animals typically show a very mild disease course.12 If HCV-specific CD8+ T cells play a role in the benign clinical course seen in chimpanzees, it could be a result of the virus' being severely constrained by CD8 mediated mutations, but it could also be due to the lack of recognizable antigen presented by hepatocytes to the T cells, and thus a lack of T-cell–mediated killing of hepatocytes. Regardless of which scenario reflects the reality of human HCV infection, a correlation between recipient-derived, donor-restricted CD8+ T cells and the clinical course of posttransplantation hepatitis C needs to be established in order to move forward to using these cells in immunotherapy.
In addition to possible clinical implications, the findings presented by Rosen et al. also present an opportunity to further evaluate the role of the liver as an immune organ. In recent years it has become increasingly clear that the liver is among the immunologically most interesting and potent organs, rivaled only by what were considered the “true” immune organs, such as thymus and lymph nodes.13 Importantly, it has been demonstrated that priming of naive T cells in the liver is likely a rather frequent event, mediated not only by the usual suspects of professional antigen presenting cells such as dendritic cells or macrophage related cell populations, but also by hepatocytes.14 Furthermore, it has been suggested that priming of naive T cells in the liver often results in deletion of the respective T-cell clones rather than clonal expansion,13, 15, 16 and this was interpreted as beneficial in the context of the large number of food and environmental antigens reaching the liver through the portal system. Deletion of T-cell clones specific for frequently ingested antigens would be important for the prevention of allergic reactions. But how does this relate to HCV infection and the study by Rosen et al.? While deletion of antigen-specific T-cell clones is beneficial when it comes to food derived antigens, this would be potentially problematic for infective agents with a strong tropism for hepatocytes.14 If such pathogens did not additionally infect professional antigen presenting cells and were not introduced in the cross-priming pathway of dendritic cells, the host immune system might develop a blind spot for them. For HCV infection, which is mostly, if not absolutely, confined to hepatocytes, the result could be the deletion of HCV-specific T-cell clones with the consequence of establishment of chronic infection. In this context, the phenomenon described by Rosen et al. could serve as an interesting model to further evaluate this hypothesis in human HCV infection. For the recipient-derived, donor-restricted CD8+ T cells, it is certain that they have been primed by antigen presenting cells from the donor liver and not by the recipients' immune system. The dynamics of these responses might give additional insight into the immunological mechanisms involved in T-cell priming under these exceptional conditions. One observation in the study by Rosen et al. is that these responses expand rather late after transplantation and reinfection, in contrast to other models of acute HCV infection where responses typically are primed and detectable within 8 weeks. For example, in patient 2, for whom serial samples were available, HCV-specific immune responses appeared in peripheral blood mononuclear cells anywhere between 8 and 20 months. It is not clear whether this delay was a consequence of immunosuppression or of the mode of T-cell priming. Even more importantly, one would want to know whether these cell populations are maintained beyond the single time points at which they were detected here and, if so, for how long. This would be relevant not only to answer the question of the effect of T-cell priming in the hepatic environment, but also to estimate the usefulness of such T-cell clones in immunotherapy.
Finally, it would be important to know whether other parts of the host-specific immune system, especially HCV-specific CD4+ T cells, are primed in a similar way. These cells have indeed been shown (by the same group) to have an impact on the clinical course of the allograft after transplantation in the HCV infected host17 and may support the function of HCV-specific CD8+ T cells.18, 19 Induction of recipient-derived, donor-restricted CD4+ T cells would foster confidence in the possibility of immunotherapy in patients with HCV infection of the allograft.
In summary, the findings by Rosen et al. demonstrate the capability of donor liver–associated cells to prime and expand naive recipient-derived CD8+ T cells specific for HCV. This finding has the potential to lead to adaptive immunotherapy in liver transplant patients with severe HCV infection of the allograft. However, it has to be established first whether such cells have the capability to influence HCV disease progression in the allograft, either by contributing to viral control or by promoting liver injury. In addition to its clinical relevance, the phenomenon of donor-restricted, recipient-derived CD8+ T cells might provide unique insights in the capabilities of the liver as an immune organ.