Prof. Dr. Percy A. Knolle
Tel +49 89 4140 - 6920
Fax +49 89 4140 - 6922
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.
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.
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.
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.
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.