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Researchers find deprived T cells allow HBV to replicate without triggering liver damage

In a study published in Nature Medicine, researchers found that when T cells’ nutrient supply was shut off, their ability to fight against hepatitis B virus infection and cause liver inflammation was disrupted.

“Hepatitis B patients usually don't have symptoms for decades, so [they] can carry the virus unknowingly and can spread it through childbirth, sexual contact or contaminated needles,” Mala K. Maini, PhD, Division of infection and immunity at the Institute of Immunity and Transplantation, University College London, United Kingdom, said in a press release. “Our work has shown that during this ‘silent phase’ of infection, specialized suppressor cells switch off the immune response by cutting off its supply of a key nutrient. This is one of the many ways the liver protects itself from inflammation and immune damage, but at the same time, prevents elimination of pathogens like hepatitis B.”

Mala K. Maini

Laura Pallett

Laura Pallett, PhD, analyzed blood samples of 138 patients with chronic HBV and compared them with 99 healthy controls. She also examined liver tissue samples from 42 patients.

The researchers found that patients in the “silent phases of infection” had high levels of granulocytic myeloid-derived suppressor cells (gMDSCs). These gMDSCs, which suppress T cells by limiting their nutrient supply, were found to accumulate in the liver with the help of hepatic stellate cells.

The gMDSCs “expanded transiently in acute resolving HBV, decreasing in frequency prior to peak hepatic injury,” according to the research.

In chronic HBV, gMDSCs increased maximally when disease phases were characterized by HBV replication without immunopathology. As this occurred, L-arginine decreased, according to the research.

“The gMDSCs suppressed both the T cells that fight hepatitis B virus and those that cause inflammation in the liver,” Pallett said in the release. “So patients with more gMDSC tended to have less liver damage but were unable to control hepatitis B virus. Women had higher levels of gMDSC than men, which fits with their threefold lower risk of developing liver inflammation from hepatitis B."

“If these cells can prevent immune cells from damaging the liver in hepatitis B patients, perhaps they could help to prevent immune rejection of transplanted livers,” Maini said. “Similarly, such suppressor cells could potentially be harnessed to protect specific organs from damage in patients with autoimmune diseases.”

The researchers concluded: “We provide in vitro and ex vivo evidence that gMDSCs potently inhibited T cells in a partially arginase-dependent manner. These data demonstrate the capacity of expanded arginase-expressing gMDSCs to regulate liver immunopathology in HBV infection.” – by Melinda Stevens

Disclosures: Maini reports consulting, advising and being an education committee member for the development of novel immunotherapeutic strategies for HBV for Bristol-Myers Squibb, Gilead, Immune Targeting Systems, MedImmune, Roche and Transgene. Please see the full study for a list of all other authors’ relevant financial disclosures.