Regulation of CD8 T cell dysfunction during a chronic viral infection

After an acute infection or vaccination, antigen-specific CD8 T cells undergo memory differentiation once the pathogen has been completely cleared. Memory CD8 T cells acquire cardinal properties that allow them to confer long-term protection, including antigen-independent homeostasis and self-renewal, rapid reacquisition of effector functions and the ability to mount a rapid, potent secondary response. During a chronic viral infection, however, the pathogen is not cleared, and this appears to drive antigen-specific CD8 T cells down an altered path of differentiation. During chronic viral infection, antigen-specific CD8 T cells become functionally exhausted, in which they progressively lose effector function and upregulate the expression of multiple inhibitory receptors. Specific memory defects also occur, as exhausted CD8 T cells do not use the IL-7/IL-15 pathway efficiently. Antigen load and lack of CD4 help correlate to the severity of dysfunction, and gene expression studies show that the differentiation of exhausted CD8 T cells may be regulated by a unique transcriptional program. However, the exact pathways and mechanisms that directly regulate the differentiation of dysfunctional CD8 T cells during chronic viral infection are not clear. In this work, we examine transcriptional, homeostatic and ‘inflammatory’ vs. antigenic regulation of functional exhaustion. Through a system of partial and total conditional deletion, we identify the transcriptional repressor Blimp-1 as an important regulator of functional exhaustion and repressor of memory differentiation. We also describe a key memory property defect and the mechanism by which exhausted antigen-specific CD8 T cells are maintained during chronic infection. Lastly, we show that prolonged, pathogen-induced ‘inflammation’ alone can alter memory CD8 T cell differentiation, while other signals such as antigen may be necessary to lead to the loss of effector functon and high expression of inhibitory receptors that are hallmarks of functional exhaustion. Together, we have identified multiple pathways at different levels of regulation that further our understanding of how functional exhaustion may occur during chronic viral infection