Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization.
The liver is tolerogenic in many situations, including as an allograft and during the response to allogeneic MHC expressed on hepatocytes. The majority of data that address this issue focus on endogenous Ags. Little is known about CD4(+) T cells and their fate under tolerizing conditions, especially with respect to fully differentiated CD4(+) effector T cells. In this study, we used the adoptive transfer of populations of TCR-transgenic CD4(+) T cells, skewed toward the Th1 or Th2 phenotype, to test whether either apoptotic or immune deviation mechanisms apply to cytokine-producing CD4(+) T cells that enter the liver. After transfer, Th1 and Th2 cells could be detected up to 25 days in lymphoid organs and the liver. Intravenous high dose Ag application resulted in accumulation, proliferation, and subsequent deletion of effector cells within the liver. Th1 cells lost their capacity to produce cytokines, whereas IL-4 expression was sustained within Th2 cells from the liver. However, there was no evidence for a deviation of Th1-programmed cells toward a Th2 (IL-4) or regulatory T cell (IL-10) pattern of cytokine expression. We used isolated populations of liver-derived APCs to test whether the liver had the capacity to impose a bias toward IL-4 expression in T cells. These experiments showed that liver sinusoidal endothelial cells selectively suppress the expansion of IFN-gamma-producing cells, yet they promote the outgrowth of IL-4-expressing Th2 cells, creating an immune suppressive milieu within this organ. These data suggest that presentation of Ags in the liver leads to modulation of immune response in terms of quantity and quality.
Klugewitz
Katja
K
Section of Immunobiology, Yale University Medical School, New Haven, CT 06520, USA. klugewitz@drfz.de
Blumenthal-Barby
Friderike
F
Schrage
Arnhild
A
Knolle
Percy A
PA
Hamann
Alf
A
Crispe
Ian Nicholas
IN
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D013997:Time Factors
C111390:OVA 323-339; D010446:Peptide Fragments; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin