Alloreactive (CD4-Independent) CD8+ T Cells Jeopardize Long-Term Survival of Intrahepatic Islet Allografts

Lunsford, Keri E.; Jayanshankar, Kartika; Eiring, Anna M.; Horne, Phillip H.; Koester, Mitchel A.; Gao, Donghong; Bumgardner, Ginny L.

doi:10.1111/j.1600-6143.2008.02219.x

Cited by 14 publications

(12 citation statements)

References 67 publications

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“…However, more rapid CD8 + T cell response with increased expression of CD69 matches our findings for CD69 expression on day 3. Furthermore, expression of CD69 on peripheral CD8 + cells after kidney transplantation in vivo correlates closely with acute rejection of allografts, and alloreactive CD8 + T cells are considered responsible for late rejection reactions, resulting in diminished longterm survival …”

Section: Discussionmentioning

confidence: 99%

Hepatocyte‐induced CD4+ T cell alloresponse is associated with major histocompatibility complex class II up‐regulation on hepatocytes and suppressible by regulatory T cells

et al. 2018

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Hepatocyte transplantation is a promising therapeutic approach for various liver diseases. Despite the liver's tolerogenic potential, early immune‐mediated loss of transplanted cells is observed, and longterm acceptance has not been achieved yet. Patients deemed tolerant after liver transplantation presented an increased frequency of regulatory T cells (Tregs), which therefore also might enable reduction of posttransplant cell loss and enhance longterm allograft acceptance. We hence characterized hepatocyte‐induced immune reactions and evaluated the immunomodulatory potential of Tregs applying mixed lymphocyte cultures and mixed lymphocyte hepatocyte cultures. These were set up using peripheral blood mononuclear cells and primary human hepatocytes, respectively. Polyclonally expanded CD4+CD25highCD127low Tregs were added to cocultures in single‐/trans‐well setups with/without supplementation of anti‐interferon γ (IFNγ) antibodies. Hepatocyte‐induced alloresponses were then analyzed by multicolor flow cytometry. Measurements indicated that T cell response upon stimulation was associated with IFNγ‐induced major histocompatibility complex (MHC) class II up‐regulation on hepatocytes and mediated by CD4+ T cells. An indirect route of antigen presentation could be ruled out by use of fragmented hepatocytes and culture supernatants of hepatocytes. Allospecific proliferation was accompanied by inflammatory cytokine secretion. CD8+ T cells showed early up‐regulation of CD69 despite lack of cell proliferation in the course of coculture. Supplementation of Tregs effectively abrogated hepatocyte‐induced alloresponses and was primarily cell contact dependent. In conclusion, human hepatocytes induce a CD4+ T cell alloresponse in vitro, which is associated with MHC class II up‐regulation on hepatocytes and is susceptible to suppression by Tregs. Liver Transplantation 24 407–419 2018 AASLD.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte‐induced CD4+ T cell alloresponse is associated with major histocompatibility complex class II up‐regulation on hepatocytes and suppressible by regulatory T cells

et al. 2018

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“…For example, we have previously reported that CD4 + T cell depletion of islet transplant recipients (whether transplanted by intraportal or kidney subcapsular route) in the same MHC recipient/donor combination as hepatocyte transplant recipients in the current study results in prolonged allograft survival (>70 days) 51 . These long-term surviving islet allografts remain susceptible to rejection since, adoptive transfer of alloreactive CD4-independent CD8 + T cells (stimulated by hepatocyte transplant) results in rejection 52 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…In our model, allospecific CD8 + cytotoxic T lymphocytes (CTL) effector function is significantly enhanced in magnitude and persistence when primed in the presence of CD4 + T cells. However, our studies utilizing transgenic CD8 + T cells suggest that the enhanced cytotoxic effector activity generated in the presence of CD4 + T cells was not a result of enhanced proliferation, precursor frequency, or CD8 + T cell trafficking to the liver sinusoids (site of cellular transplantation) (17, 18). This led us to investigate the hypothesis that CD8 + T cell cytotoxic effector mechanisms which develop in CD4-replete conditions are fundamentally different, and perhaps more complex, from those which develop in CD4-deficient conditions.…”

Section: Introductionmentioning

confidence: 88%

Cytotoxic Effector Function of CD4-Independent, CD8+ T Cells Is Mediated by TNF-α/TNFR

et al. 2012

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Background Liver parenchymal cell allografts initiate both CD4-dependent and CD4-independent, CD8+ T cell-mediated acute rejection pathways. The magnitude of allospecific CD8+ T cell in vivo cytotoxic effector function is maximal when primed in the presence of CD4+ T cells. The current studies were conducted to determine if and how CD4+ T cells might influence cytotoxic effector mechanisms. Methods Mice were transplanted with allogeneic hepatocytes. In vivo cytotoxicity assays and various gene-deficient recipient mice and target cells were utilized to determine the development of Fas-, TNF-α-, and perforin-dependent cytotoxic effectors mechanisms following transplantation. Results CD8+ T cells maturing in CD4-sufficient hepatocyte recipients develop multiple (Fas-, TNF-α-, and perforin-mediated) cytotoxic mechanisms. However, CD8+ T cells, maturing in the absence of CD4+ T cells, mediate cytotoxicity and transplant rejection that is exclusively TNF-α/TNFR-dependent. To determine the kinetics of CD4-mediated help, CD4+ T cells were adoptively transferred into CD4-deficient mice at various times posttransplant. The maximal influence of CD4+ T cells on the magnitude of CD8-mediated in vivo allocytotoxicity occurs within 48 hours. Conclusion The implication of these studies is that interference of CD4+ T cell function by disease or immunotherapy will have downstream consequences on both the magnitude of allocytotoxicity as well as the cytotoxic effector mechanisms employed by allospecific CD8+ cytolytic T cells.

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Alloreactive (CD4-Independent) CD8+ T Cells Jeopardize Long-Term Survival of Intrahepatic Islet Allografts

Cited by 14 publications

References 67 publications

Hepatocyte‐induced CD4+ T cell alloresponse is associated with major histocompatibility complex class II up‐regulation on hepatocytes and suppressible by regulatory T cells

Hepatocyte‐induced CD4+ T cell alloresponse is associated with major histocompatibility complex class II up‐regulation on hepatocytes and suppressible by regulatory T cells

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

Cytotoxic Effector Function of CD4-Independent, CD8+ T Cells Is Mediated by TNF-α/TNFR

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