Dysfunctional T cells in hepatitis fail to induce transcription factor

Last Updated: 2014-09-17

By Will Boggs MD

NEW YORK (Reuters Health) - Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction, researchers have found - but whether boosting T-bet levels in newly infected patients will help eliminate the virus remains to be seen.

T-bet is a transaction factor that regulates the production of interferon-gamma and cytotoxic molecules, the German researchers report.

"Our data provide for the first time evidence for the central role of T-bet in self-limiting human viral infections and for deficient T-bet induction in virus-specific CD8 T cells as a mechanism associated with viral persistence," they said in a paper online September 15 in The Journal of Experimental Medicine.

And, they reported, "T-bet induction by IL-2 and co-stimulation with IL-12 restored function in previously exhausted virus-specific CD8 T cells," suggesting that their findings could lead to future therapies.

"Since there is effective therapy available for chronic HCV infection I doubt IL-2+IL-12 will find its way into HCV treatment," said coauthor Dr. Peter D. Kurktschiev from Ludwig-Maximilians-University and University Hospital Munich in email to Reuters Health. "However, chronic HBV infection is still a challenge and needs new treatment options."

"This treatment could be used for other viral infections as well (HSV, CMV, HIV), as these effects are not specific for HBV or HCV infection," Dr. Kurktschiev said.

Virus-specific CD8 T cells become increasingly dysfunctional in chronic HBV and HCV infection. To learn more about the extent to which impaired regulation of T-bet might be involved in the development of these chronic infections, Dr. Kurktschiev and colleagues studied patients with acute infection.

T-bet was highly expressed during acute resolving HBV and HCV infection and correlated with spontaneous resolution of the infection.

In contrast, deficiencies in T-bet in early acute HCV infection were followed by chronic-evolving infection.

In further experiments, the researchers were able to induce T-bet by interleukin-2, and this facilitated antigen-specific production of interferon-gamma in HBV-specific CD8 T cells in cooperation with interleukin-12.

Moreover, high expression of T-bet was associated with strong antigen-specific proliferation of CD8 T cells, which is key to the generation of sufficient amounts of effector cells for control of the virus.

"Our initial results were in consent with previous findings where T-bet expression correlated with improved functionality of CD8 T-cells," Dr. Kurktschiev said. "T-bet has predictive value during acute HCV infection and could be of use for monitoring the success of antiviral therapy as well."

Dr. Eui-Cheol Shin from the Graduate School of Medical Science & Engineering, KAIST, Daejeon, Korea, has also researched dysfunctional T cells in hepatitis. He told Reuters Health, "In this paper, the authors showed that a lack of T-bet expression is associated with dysfunctional CD8+ T cells. This finding is surprising because CD8+ T cell dysfunction is regulated by a transcription factor, T-bet, at the transcriptional level."

"However, it is unclear if IL-2/IL-12 will be useful for patients with chronic hepatitis B or C," Dr. Shin said. "Functional restoration of dysfunctional T cells is a different story from prevention of T cell dysfunction. In addition, we also consider a possibility of Th1-mediated immunological diseases, as IL-12 induces Th1 responses."

SOURCE: http://bit.ly/1o3V0nS

J Exp Med 2014.