A team of researchers from The Wistar Institute has identified a protein that could serve as a target for reprogramming immune system cells exhausted by exposure to chronic viral infection into more effective "soldiers" against certain viruses like HIV, hepatitis C, and hepatitis B, as well as some cancers, such as melanoma.
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."