Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver.
The mechanisms of tolerance in the liver that limit susceptibility to food allergy and that mediate the acceptance of liver transplants, even with a complete major histocompatibility complex (MHC) mismatch, remain poorly defined. Here we report that in a model of liver-directed gene transfer, cytotoxic T lymphocyte (CTL) responses to non-self antigens are controlled by hepatic regulatory T cells (Tregs) that secrete the immunosuppressive cytokine interleukin (IL)-10 in response to the antigen. In addition, Kupffer cells (KCs), normally thought to initiate immune responses, are rendered tolerogenic in this context. The depletion of KCs results in a complete abrogation of IL-10 production by hepatic Tregs, indicating an interaction between Tregs and KCs in the induction of tolerance.


CONCLUSIONS
Our study suggests that hepatic Tregs together with KCs create a local suppressive microenvironment that prevents the establishment of the CTL response. These mechanisms provide pivotal insights and may prove instrumental in the tolerization toward non-self therapeutic proteins delivered to the liver.
Breous
Ekaterina
E
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Somanathan
Suryanarayan
S
Vandenberghe
Luk H
LH
Wilson
James M
JM
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D000515:alpha 1-Antitrypsin / Q000276:immunology
C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D016753:Interleukin-10