Immune Cells Fighting Chronic Infections become 'Exhausted'

[Guest guest]

The Wistar Institute

Immune cells fighting chronic infections become

progressively 'exhausted,' ineffective

Potential interventions to restore disease-fighting capability

outlined

(PHILADELPHIA) – A new study of immune cells battling a chronic

viral infection shows that the cells, called T cells, become

exhausted by the fight in specific ways, undergoing profound changes

that make them progressively less effective over time.

The findings also point to interventions that would reverse the

changes, suggesting that novel therapies could be developed to

reinvigorate T cells that become depleted in their struggle against

a virus. Alternatively, strategies that would intentionally trigger

the immune-dampening mechanisms explored in the study could prove

useful in countering autoimmune disorders in which the immune system

is inappropriately activated.

Although the experiments were conducted in mice, the problem of T-

cell exhaustion has also been identified in HIV, hepatitis B, and

hepatitis C infections in humans, as well as some cancers, such as

melanoma. A report on the study results appears in the current issue

of Immunity, published online October 18.

" We knew that T cells responding to chronic infections become

progressively compromised in many of their functional properties, "

says E. Wherry, Ph.D., an assistant professor in the Immunology

Program at The Wistar Institute and lead author on the Immunity

study. " Put simply, the T cells become exhausted as time passes.

What we wanted to learn in our study was what the specific problems

were with these cells and whether their depleted state could be

reversed. "

Using a technique called gene-expression profiling, Wherry and his

colleagues identified 490 genes whose activity in T cells is altered

during a chronic viral infection. Closer study at different time

points using a 22-gene subset of the larger group of genes provided

molecular signatures of progressive T-cell exhaustion. Only a few

changes in the activity of the 22 genes were seen at the end of the

first week of infection, increasing to 9 differences at two weeks,

18 differences at one month, and 21 differences at two months. At

the end of two months, T cells contending with a chronic infection

were sluggish metabolically and immunologically unresponsive to

stimulus.

One gene identified as playing a central role in this process is

called PD-1, which codes for an inhibitory receptor on the surface

of the T cells. By blocking PD-1 in vivo, the researchers found they

could alleviate T-cell exhaustion, get more functional T cells, and

control the infection better.

" Blocking this one pathway partially reverses T-cell exhaustion in

some settings, suggesting that we may be able to intervene to

reinvigorate depleted immune cells, " says Wherry. " The T cells

undergo many changes during chronic infections, however, so that it

will be important to learn how to treat them for multiple problems. "

Wherry notes that the mechanisms involved in T-cell exhaustion also

have important upsides.

" The flip side of this process is that the immune system has

developed an effective way to turn off its response to a stimulus –

which is exactly what one wants to do in the case of autoimmunity, "

he says.

He points out, too, that the energy outlay during the acute phase of

the immune system's response to an infection is enormous – and

fundamentally unsustainable.

" In the first week of an immune response to a virus, T cells can

divide every four to six hours, as fast as any other mammalian cell

at any time during development, " Wherry says. " In terms of their

rate of division, T cells are in the same category as cells in the

earliest stages of embryonic development. The energy involved in

doing this is extraordinary, and the body can't keep that up for an

extended period of time. "