Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells

TY - JOUR

T1 - Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells

AU - Pallett, Laura J.

AU - Gill, Upkar S.

AU - Quaglia, Alberto

AU - Sinclair, Linda V.

AU - Jover-Cobos, Maria

AU - Schurich, Anna

AU - Singh, Kasha P.

AU - Thomas, Niclas

AU - Das, Abhishek

AU - Chen, Antony

AU - Fusai, Giuseppe

AU - Bertoletti, Antonio

AU - Cantrell, Doreen A.

AU - Kennedy, Patrick T.

AU - Davies, Nathan A.

AU - Haniffa, Muzlifah

AU - Maini, Mala K.

PY - 2015/5/11

Y1 - 2015/5/11

N2 - Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: the virus can either replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the potential for myeloid-derived suppressor cells (MDSCs) to suppress T cell-mediated immunopathology in this setting. Granulocytic MDSCs (gMDSCs) expanded transiently in acute resolving HBV, decreasing in frequency prior to peak hepatic injury. In persistent infection, arginase-expressing gMDSCs (and circulating arginase) increased most in disease phases characterized by HBV replication without immunopathology, whilst L-arginine decreased. gMDSCs expressed liver-homing chemokine receptors and accumulated in the liver, their expansion supported by hepatic stellate cells. We provide in vitro and ex vivo evidence that gMDSCs potently inhibited T cells in a partially arginase-dependent manner. L-arginine-deprived T cells upregulated system L amino acid transporters to increase uptake of essential nutrients and attempt metabolic reprogramming. These data demonstrate the capacity of expanded arginase-expressing gMDSCs to regulate liver immunopathology in HBV infection.

AB - Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: the virus can either replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the potential for myeloid-derived suppressor cells (MDSCs) to suppress T cell-mediated immunopathology in this setting. Granulocytic MDSCs (gMDSCs) expanded transiently in acute resolving HBV, decreasing in frequency prior to peak hepatic injury. In persistent infection, arginase-expressing gMDSCs (and circulating arginase) increased most in disease phases characterized by HBV replication without immunopathology, whilst L-arginine decreased. gMDSCs expressed liver-homing chemokine receptors and accumulated in the liver, their expansion supported by hepatic stellate cells. We provide in vitro and ex vivo evidence that gMDSCs potently inhibited T cells in a partially arginase-dependent manner. L-arginine-deprived T cells upregulated system L amino acid transporters to increase uptake of essential nutrients and attempt metabolic reprogramming. These data demonstrate the capacity of expanded arginase-expressing gMDSCs to regulate liver immunopathology in HBV infection.

UR - https://www.scopus.com/pages/publications/84930651350

U2 - 10.1038/nm.3856

DO - 10.1038/nm.3856

M3 - Article

C2 - 25962123

AN - SCOPUS:84930651350

SN - 1078-8956

VL - 21

SP - 591

EP - 600

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -