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
Scientists unlock ability to generate new sensory hair cells
22.02.2017 | Brigham and Women's Hospital
New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
22.02.2017 | Power and Electrical Engineering
22.02.2017 | Life Sciences
22.02.2017 | Physics and Astronomy