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Oct 19, 2007

Molecular Signatures of Progressive T-cell Exhaustion Revealed

  • A group of researchers say that they have identified a subset of genes that change with T-cell exhaustion, which occurs during chronic viral infection. They suggest that therapies could be developed to reinvigorate T cells. Alternatively, they add, methods that intentionally trigger the immune-dampening mechanisms explored in the study could prove useful in countering autoimmune disorders.

    The scientists found 490 genes whose activity in T cells is altered during a chronic viral infection. A closer look at different time points using a 22-gene subset 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 nine differences two weeks later, 18 at one month, and 21 differences after two months, according to the investigators. At this point, T cells contending with a chronic infection were metabolically sluggish and immunologically unresponsive to stimulus, they add.

    The research group identified one gene as playing a central role in this process. PD-1 codes for an inhibitory receptor on the surface of the T cells. By blocking PD-1 in vivo, the team found that 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 E. John Wherry, Ph.D., an assistant professor in the immunology program at The Wistar Institute and lead author.

    “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,” Dr. Wherry asserts.

    Mechanisms involved in T-cell exhaustion also have important upsides, Dr. Wherry continues. “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.”

    Scientists from Emory University School of Medicine, Yale University Medical School, Dana-Farber Cancer Institute, Fred Hutchinson Cancer Research Center, and the NIH also contributed to this study. A paper describing the findings appears in the online October 18 issue of Immunity.



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