Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

Abstract

Background The liver immune environment is tightly regulated to balance immune activation with immune tolerance. Understanding the dominant immune pathways initiated in the liver is important since the liver is a site for cell transplantation, such as for islet and hepatocyte transplantation. The purpose of this study is to examine the consequences of alloimmune stimulation when allogeneic cells are transplanted to the liver in comparison to a different immune locale, such as the kidney. Methods We investigated cellular and humoral immune responses when allogeneic hepatocytes are transplanted directly to the recipient liver by intraportal injection. A heterotopic kidney engraftment site was used for comparison to immune activation in the liver microenvironment. Results Transplantation of allogeneic hepatocytes delivered directly to the liver, via recipient portal circulation, stimulated long-term, high magnitude CD8+ T cell-mediated allocytotoxicity. CD8+ T cells initiated significant in vivo allocytotoxicity as well as rapid rejection of hepatocytes transplanted to the liver even in the absence of secondary lymph nodes or CD4+ T cells. In contrast, in the absence of recipient peripheral lymphoid tissue and CD4+ T cells, CD8-mediated in vivo allocytotoxicity was abrogated and rejection was delayed when hepatocellular allografts were transplanted to the kidney subcapsular site. Conclusions These results highlight the CD8-dominant proinflammatory immune responses unique to the liver microenvironment. Allogeneic cells transplanted directly to the liver do not enjoy immune privilege but rather require immunosuppression to prevent rejection by a robust and persistent CD8‐dependent allocytotoxicity primed in the liver.

Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection

“…To determine if the observed in vivo allocytotoxicity is CD8 dependent, a cohort of WT recipients were treated with anti-CD8 mAb 12 d prior to the day 7 in vivo allocytotoxicity assay; depletion of recipient CD8 1 T cells significantly reduced allogeneic allocytotoxicity (p < 0.0001). This confirmed that in vivo allocytotoxicity is predominantly CD8 mediated and that low residual allocytotoxicity in WT hosts is likely Ab mediated, as previously reported (16). In contrast, Ja18 KO recipients do not produce significant alloantibody after transplant (44).…”

“…CD4-independent, CD8 1 T cellmediated allograft rejection is resistant to costimulatory blockade and implicated in the rejection of hepatocellular allografts (13,19), intestinal allografts (20), skin allografts (21,22), and cardiac allografts (23,24). In addition, we have reported that the liver microenvironment is sufficient to prime CD8 1 T cells in the absence of both CD4 1 T cells and secondary lymphoid tissue (16). Alloprimed CD4-independent CD8 1 T cells in hepatocyte allograft recipients are distinguished by TNF-aÀdependent cytotoxic effector function that peaks on day 5 posttransplant compared with CD4-dependent, CD8 1 T cellmediated Fas ligand (FasL) and perforin-dependent cytotoxicity that peaks on posttransplant day 7 (17,18).…”

Chronic Hepatitis C Virus Infection Impairs M1 Macrophage Differentiation and Contributes to CD8+ T-Cell Dysfunction

“…By virtue of their location (lining the walls of liver sinusoids), KCs interact routinely with circulating immune cells in the blood [17]. Such interactions, including that of infiltrating macrophages, may contribute to a broad dysfunction of the circulating CD8 + T-cell pool that we and others have observed in chronic HCV infection [18,19,20,21]. While impaired HCV-specific CD8 + T-cells pose an impediment to virus control in chronic infection, a broad dysfunction of the T-cell compartment suggests an influence from antigen-independent cell-to-cell interactions or local and systemic microenvironments.…”

Critical Role of Macrophage FcγR Signaling and Reactive Oxygen Species in Alloantibody-Mediated Hepatocyte Rejection

“…Once anti-CD8 mAb treatment was stopped though, hepatocyte rejection occurred in all recipients by day 63 indicating that long-term engrafted hepatocytes remain vulnerable to (CD8-mediated) hepatocyte rejection. The occurrence of rejection 14 days after cessation of anti-CD8 mAb treatment was expected since this time-frame corresponds with reconstitution of CD8 + T cells in the periphery and transplanted hepatocytes are highly susceptible to CD8 + T cell mediated rejection (13, 43–45). Our data is consistent with the interpretation that, despite the presence of high alloantibody titers (Figure 3C), transplanted allogeneic hepatocytes are not rejected in CD8-depleted recipients with impaired FcγR signaling.…”