Scientists find key to strengthening immune response to chronic infection

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.

Source: The Wistar Institute