Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling.
OBJECTIVE
Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH.


METHODS
To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments.


RESULTS
In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. In contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma.


CONCLUSIONS
NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.
Kido
Masahiro
M
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Watanabe
Norihiko
N
Okazaki
Taku
T
Akamatsu
Takuji
T
Tanaka
Junya
J
Saga
Kazuyuki
K
Nishio
Akiyoshi
A
Honjo
Tasuku
T
Chiba
Tsutomu
T
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D034961:Antigens, Nuclear / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005756:Gastritis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D061026:Programmed Cell Death 1 Receptor; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013934:Thymectomy
D000974:Antibodies, Antinuclear; D000943:Antigens, Differentiation; D034961:Antigens, Nuclear; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor