The immune system is able to kick out many viral invaders after a few days to weeks. But others, from herpes to hepatitis C, can come to be in a permanent standoff with the immune system, controlled but not eliminated altogether.

In chronic viral infection, CD8 "killer" T cells enter a state that has been called "exhausted." Such cells no longer produce cytokines to any appreciable effect, and many scientists thought they were incapable of dividing.

But a team from the Swiss Vaccine Research Institute has demonstrated that rather than being incapable of fighting any longer, such cells may have mastered the fine art of compromise – managing to keep chronic viral infection at bay without causing too much collateral damage to host tissue. T cells secrete proinflammatory cytokines, and chronic inflammation contributes to a host of diseases.

Although they do not directly identify drug targets or cell populations that could be used to fight chronic infections, the findings, corresponding author Dietmar Zehn told BioWorld Today, "create a different way of thinking" about what T cells are up to in chronic infections – one that could ultimately change the practical approaches toward such infections.

"We always thought that these exhausted T cells are a dead end" in terms of actually fighting infections, Zehn said. But "they may not be as useless as we think."

In their work, which was published in the May 5, 2013, online issue of Nature Immunology, Zehn and his team showed that some exhausted T cells are capable of rapidly dividing once more, and mounting an immune response, if they are transplanted into naïve mice that are then infected with the virus they recognize. Moreover, that was true even if the mice were infected after a delay, which implies that there must be memory-like T cells in the pool of exhausted cells – another contradiction of currently accepted wisdom.

In their experiments, Zehn and his team first infected mice with a strain of lymphocytic choriomeningitis virus (LCMV) that causes chronic infection. About a month after such an infection was first established, they isolated supposedly exhausted T cells from the blood of the animals and transferred them into mice that had not been exposed to LCMV. They then infected those animals with LCMV, either fairly soon or a few weeks after the transfer.

In both cases, the supposedly exhausted T cells were able to start dividing again when they encountered LCMV. Controls showed that even cells with a high affinity for LCMV showed the ability to begin dividing once more, and that the cells that could jump-start the immune response after transplantation were not just the youngest cells that had not yet had a chance to exhaust themselves, but older cells, too.

Most of the resulting daughter cells, though, did not re-acquire the virus-fighting profile of T cells in an acute infection. The proportion of cells expressing both interferon-gamma and TNF remained low, which is consistent with the idea that such cells are trying to strike a balance between viral control and damage to mouse tissues.

T cells from chronically infected mice also kept expressing PD-1 , a surface receptor that inhibits T cells and is part of the immune system's way of keeping the response to infections from spiraling out of control. Blockers for PD-1 and its ligand are currently in development to increase the immune system response to tumors. (See BioWorld Insight, April 15, 2013.)

Zehn said one implication of his team's results is that "we should be careful using phenotypic markers as surrogate indicators for T-cell function. . . . We essentially showed that cells which show a phenotype based on which we would have thought that they are not functional" – namely, PD-1 expression – "appear to be much more functional than anticipated."

He added that "so far, we have stayed pretty much at the population level," demonstrating that transplantation can lead some exhausted T cells to start dividing again. His team wants to delve into the subpopulations of T cells to see what distinguishes exhausted T cells that can be awoken from their nap from those that are well and truly done with dividing. Discovering "what the precursors of these cells that re-expand look like," he said, might enable researchers to coax them into mounting further immune attacks – perhaps, if they can be timed right, to eliminate stubborn infections altogether.