The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity

Abstract

Hepatic immunobiology is paradoxical: although the liver possesses unusual tolerogenic properties, it is also the site of effective immune responses against multiple pathogens and subject to immune-mediated pathology. The mechanisms underlying this dichotomy remain unclear. Following previous work demonstrating that the liver may act as a site of primary T cell activation, we demonstrate here that the balance between immunity and tolerance in this organ is established by competition for primary activation of CD8 + T cells between the liver and secondary lymphoid tissues, with the immune outcome determined by the initial site of activation. Using a transgenic mouse model in which antigen is expressed within both liver and lymph nodes, we show that while naive CD8 + T cells activated within the lymph nodes were capable of mediating hepatitis, cells undergoing primary activation within the liver exhibited defective cytotoxic function and shortened half-life and did not mediate hepatocellular injury. The implications of these novel findings may pertain not only to the normal maintenance of peripheral tolerance, but also to hepatic allograft tolerance and the immunopathogenesis of chronic viral hepatitis.

Reply

“…The important publication by Bowen et al 6 did not use danger signals, but rather induced a self-limited hepatitis, followed by immune tolerance, thereby, rather supporting our statement.…”

Serum glycan as a prognostic marker in patients with advanced hepatocellular carcinoma treated with sorafenib

“…1). The important publication by Bowen et al 6 did not use danger signals, but rather induced a self-limited hepatitis, followed by immune tolerance, thereby, rather supporting our statement.Regarding the nature of the inducing autoantigen, we could show that similar antigens can induce AIH as well as identical antigens. However, we did not try CYP2D6 as an orthologous autoantigen.…”

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

“…This raises the question of the physiological benefit of such recruitment. There are indications that activation of naive CD8 ϩ T cells is not confined to the lymph nodes; naive T cells can be primed following an encounter with Ag in the liver (27). This is unlikely in the influenza model, unless circulating Ag-presenting dendritic cells from the lung are being trapped in that site.…”

“…The liver is continuously exposed to potential pathogens and probiotic and food-derived Ags delivered in the blood via the portal vein. This is reflected in the liver's multifaceted capabilities, including unique tolerogenic properties (23,25,26), the initiation (27) and progression of immune responses against diverse pathogens, and the ability to withstand immune-mediated pathology and regenerate itself after parenchymal injury (28 -31).…”