Help and suppression in liver tolerance

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Description: Liver tolerance was first identified in the 1960s in the context of experimental liver transplantation. In many species, an allogeneic liver transplant will survive in an immune-competent recipient, without immunosuppression. This reveals an underlying bias towards immune tolerance to multiple liver antigens, including those encoded by transgenes (neo-self antigens), viruses and parasites. Many mechanisms have been proposed to explain liver tolerance, but there is no satisfactory model that unites them. The purpose of this project is to test two potential mechanisms and determine if they are mechanistically linked. Abundant evidence, including some generated by our lab, supports the concept that failure of CD8+ T  cell immunity in the liver is due to lack of CD4+ T cell help, resulting in CD8+ T cell loss of function  and clonal exhaustion. Other evidence, including Preliminary Data we present here, suggests that  immunosuppressive molecules are induced in liver cells, in particular Liver Sinusoidal Endothelial  Cells, by Interferon‐gamma. Our central novel idea is that these two mechanisms of tolerance are  linked, and the Preliminary Data strongly implicate Liver Sinusoidal Endothelial cells. In Specific Aim  1 we will test the hypothesis that Liver Sinusoidal Endothelial Cells are central in controlling CD4+ T  cell activation and thereby immunity versus tolerance, while in Specific Aim 2 we will test whether  Interferon‐gamma regulates the function of Liver Sinusoidal Endothelial Cells to induce tolerance. We  have optimized an AAV‐based model of liver tolerance to test these concepts, however the possibility  remains open that they are unique to the model. Therefore in Specific Aim 3 we test the same concepts  in a mouse model of Hepatitis B infection. If the concepts hold in both models, we argue that they  reveal a generally applicable mechanism of tolerance.     The relationship between IFN‐induced negative feedback, also known as Adaptive Tolerance, and  CD4+ T cell help may hold in other tissues. Therefore, clarification of this relationship will be of broad  immunological interest, and may have significance in models of infection, immunity and  immunopathology in many organ systems.