Z Gastroenterol 2015; 53 - A5_53
DOI: 10.1055/s-0034-1397257

Treg impairment is not a sufficient cause of autoimmune liver inflammation

A Laschtowitz 1, A Carambia 1, AW Lohse 1, C Schramm 1, J Herkel 1
  • 1University Hospital Hamburg-Eppendorf, Department of Medicine I, Hamburg, Germany

Background:

The role of Foxp3+ regulatory T cells (Tregs) in autoimmune hepatitis is controversial. Whereas some reports suggested that autoimmune hepatitis is caused by Treg impairment, other reports did not find such link. Here, we directly addressed this issue using a mouse model, in which tolerance to a defined autoantigen is induced in the liver through generation of antigen-specific Tregs. This model is characterised both by ectopic expression of the prototypical autoantigen myelin basic protein (MBP) in the liver and by the presence of autoreactive MBP-specific T cells, due to a transgenic T cell receptor. As a result of MBP expression in the liver, these (CRP-MBP x tg4) mice feature MBP-specific Tregs that can completely suppress MBP-induced inflammation both in the liver and in the CNS (Carambia A, et al., J Hepatol 2014; Lüth S, et al., J Clin Invest 2008).

Methods:

The functionality of Tregs and T effector cells in (CRP-MBP x tg4) mice was confirmed in vivo and in vitro. Treg impairment in these mice was induced either by 1) crossing onto hCD2-ΔkTβRII mice, in which T cells feature a dominant-negative TGFβ receptor that prevents peripheral Treg induction; or by 2) Treg depletion with the PC61 antibody.

Results:

(CRP-MBP x tg4) mice feature MBP-responsive T cells; nonetheless, these mice were completely resistant to the induction of autoimmune inflammation in liver and CNS. Tregs of (CRP-MBP x tg4) mice were functional suppressors of MBP-specific effector cells that could effectively suppress inflammatory cytokine secretion of T effector cells upon MBP-stimulation in vitro. However, Treg depletion did not abrogate disease resistance in (CRP-MBP x tg4) mice. Moreover, although hepatic Treg generation was impaired in (CRP-MBP x tg4 x hCD2-ΔkTβRII) mice displaying a dominant-negative TGFβ receptor on T cells, these mice were still completely disease resistant.

Conclusion:

Our findings confirm that Tregs are instrumental for hepatic tolerance in CRP-MBP mice. Nonetheless, Treg impairment is not a sufficient cause of autoimmune liver inflammation.

Corresponding author: Laschtowitz, Alena

E-Mail: laschtowitz@gmail.com