Effective response by key immune cells in the body, called T cells, is crucial for control of many widespread chronic viral infections such as HIV and hepatitis B and C. Virus-specific CD8 T cells, also known as "killer" T cells, often lose their ability to control viral replication and become less effective over time, a process known as T cell exhaustion.
Understanding how optimal antiviral T cell responses are suppressed in these circumstances is crucial to developing strategies to prevent and treat such persisting infections.
In the August 6 on-line issue of Immunity, the research team led by Wistar assistant professor E. John Wherry, Ph.D., describes how the protein Blimp-1 (B-lymphocyte-induced maturation protein 1) represses the normal differentiation of CD8 T cells into memory T cells, which recognize disease-causing agents from previous infections and enable the body to mount faster, stronger immune responses. The team also reports that Blimp-1 causes exhausted CD8 T cells to express inhibitory receptors, which prevent recognition of specific antigens, further weakening immune response.
The researchers describe how complete deletion of Blimp-1, which is overexpressed in CD8 T cells during chronic viral infection, reversed these aspects of T cell exhaustion. By identifying Blimp-1 as a transcription factor associated with T cell exhaustion the findings open the window for reprogramming exhausted killer T cells back into prime infection-fighting form.
"We are very excited by the identification of Blimp-1 as a key transcriptional regulator of T cell exhaustion," says senior author Wherry. "Transcription factors like Blimp-1 are key molecules involved in global control of cell fate and differentiation, and Blimp-1 in particular prevents cells from de-differentiating or re-differentiating.
"In other words," continues Wherry, "if we want to make an exhausted T cell a more effective soldier against an infection like HIV, we need to change its differentiation state. Much like scientists are now re-programming terminally differentiated tissues cells to become tissue stem cells, the identification of Blimp-1 in terminally differentiated exhausted T cells suggest that future therapeutics could target this molecule to help re-differentiate exhausted T cells into more functional antiviral effector and/or memory T cells."
To determine whether Blimp-1 expression is associated with T cell exhaustion in chronic infection, the team examined Blimp-1 expression in mouse models of acute and chronic lymphocytic choriomeningitis virus (LCMV). In the mice with acute infection, Blimp-1 decreased modestly after the first week of infection. Conversely, Blimp-1 was highly upregulated in CD8 T cells in chronically infected mice by 15 days post-infection, and remained highly expressed for at least one month. The pattern of Blimp-1 expression suggested a correlation between Blimp-1 expression and T cell dysfunction and/or terminal differentiation.
In further studies to explore how Blimp-1 expression affects T cell differentiation, the team administered LCMV to mice in which a gene encoding Blimp-1 was conditionally deleted. Results showed increased numbers of antigen-specific CD8 T cells, restoration of some key aspects of normal memory CD8 T cell differentiation, and partial restoration of antigen-specific CD8 T cell populations that were otherwise terminally differentiated and deleted during chronic viral infection.
Study investigators also included Haina Shin, Ph.D., Shawn D. Blackburn, Ph.D., Charlly Kao, Ph.D., and Jill M. Angelosanto, B.S., from the Immunology Program and Vaccine Center at Wistar; and Andrew M. Intlekofer, M.D., Ph.D., and Steven L. Reiner, M.D., from the Abramson Family Cancer Research Institute, Department of Medicine, University of Pennsylvania.
This work was funded by grants from the National Institutes of Health (AI071309 and HHSN26620050030C), the Grand Challenges in Global Health Initiative, The Dana Foundation, and The Ellison Medical Foundation.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today's Discoveries – Tomorrow's Cures.
Susan Finkelstein | EurekAlert!
Further reports about: > Blimp-1 > Blimp-1 expression > CD8 > HIV > LCMV > T cell differentiation > T cells > Wistar > antigen-specific CD8 T cell populations > biomedical research > chronic viral infection > immune cell > immune response > key molecule > medical research > mouse model > viral infection
Ambush in a petri dish
24.11.2017 | Friedrich-Schiller-Universität Jena
Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology
High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons
The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
24.11.2017 | Physics and Astronomy
24.11.2017 | Health and Medicine
24.11.2017 | Earth Sciences