Prof. Dr. Percy A. Knolle
Tel +49 89 4140 - 6920
Fax +49 89 4140 - 6922
Research Focus
The research group of Prof. Knolle focuses on understanding the local regulation of immune responses in the liver and improving adaptive T cell immunity to overcome chronic infections. Cell populations within the hepatic sinusoids are engaging circulating as well as liver-resident immune cell populations. Liver sinusoidal cells are active in regulating adaptive immunity locally in the liver.
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Although innate immunity is well preserved in the liver, the persistence of microbial infections together the extraordinary acceptance of liver transplants by the recipient´s immune system indicate that immune regulation in the liver follows particular rules. Local regulatory cues delivered by organ-resident non-immune cells as well as bone marrow derived immune cells contribute to generate a micro-environment that favours induction of immune tolerance rather than immunity.
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Liver Sinusoidal Endothelial Cells (LSECs) constitute a unique population of liver-resident cells that are most efficient in scavenging of circulating antigens and cross-presentation of these antigens on MHC I molecules to CD8 T cells. Since LSEC cross-present antigens during non-inflammatory conditions to naïve CD8 T cells but fails to elicit clonal deletion, the outcome of such T cell priming outside lymphoid tissues in the liver has remained unclear. We have discovered that T cells primed by LSEC locally under non-inflammatory conditions in the liver, i.e. liver-primed T cells, fulfill memory like function. Liver-primed T cells persist similar to central memory T cells in secondary lymphoid tissues and generate recall responses giving rise to new effector T cells. Such liver-primed T cells also provide protection against infecting viruses and bacteria thus providing the first evidence that T cells primed under non-inflammatory conditions have protective function. Furthermore, these results demonstrate that liver-primed T cells complement conventional memory T cells that are generated under inflammatory conditions. Thus, liver-primed T cells may also help to circumvent immune escape by pathogens that fail to elicit or actively escape innate immunity and induction of inflammation.
Further research into the different T cell populations in the liver are ongoing.
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Cross-presentation of soluble antigens by LSEC also entails those antigens that are released from hepatocytes. We have discovered a novel cytotoxic T cell (CTL) effector function that is operative in the liver and eliminates virus-infected hepatocytes. Key to this non-canonical CTL effector function is the CTL activation by LSEC cross-presenting virus-derived antigens from infected hepatocytes. In the absence of direct MHC I-restricted antigen recognition by virus-specific CTLs the infected hepatocytes are killed through TNF released from CTLs activated by cross-presenting LSECs. TNF selectively kills infected hepatocytes because of a so far undefined change in the signaling characteristics downstream of the TNF-R that results in pro-apoptotic signaling eventually leading to caspase-induced hepatocyte death.
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The hepatic microenvironment is limiting local T cell proliferation by depleting essential amino acids, release of inhibitory molecules and delivery of death-inducing signals. Together, these regulatory cues provide a strong limitation to local proliferation of T cells in the liver, which renders immunotherapy in the liver particularly difficult. We have discovered that prolonged inflammatory signaling creates a so far unrecognized anatomic compartment within liver tissue that is formed by myeloid cells. These intrahepatic myeloid cell aggregates support local T cell expansion (iMATE) presumably by generating a cocoon-like structure that prevents hepatic regulatory cues to affect T cell proliferation within iMATEs. iMATEs induce a dramatic expansion of T cells in the liver and thereby generate sufficient numbers of T cells that can overcome even chronic viral infection. Thus, iMATEs constitute a novel strategy for achieving therapeutic vaccination against chronic viral infection of the liver.
