E. John Wherry

T cell dysfunction is common during chronic infections and can prevent optimal immunity.  This “exhaustion” is characterized by T cells that lose the ability to perform effector functions efficiently, that have low proliferative capacity and that have poor survival following antigen stimulation.  Exhausted CD8⁺ T cells also co-express multiple cell surface inhibitory receptors that negatively regulate the function of these cells.  Ongoing transcriptional profiling studies are demonstrating that exhausted CD8 T cells are in a distinct differentiation state compared to naïve or functional effector or memory CD8 T cells, but the underlying transcriptional control mechanisms leading to this altered state of differentiation have not been fully delineated.  The work presented will outline our current studies on the transcriptional control of T cell exhaustion during chronic viral infection.  Studies discussed will include work on Blimp-1, T-bet and the transcriptional profiles of exhausted CD8 T cells.  For example, our work recently uncovered a role for the transcription factor Blimp-1 in CD8⁺ T cell exhaustion during chronic viral infection.  Blimp-1 repressed key aspects of normal memory CD8⁺ T cell differentiation and promoted high expression of inhibitory receptors during chronic infection.  These cardinal features of CD8⁺ T cell exhaustion were corrected by conditionally deleting Blimp-1.  Although high expression of Blimp-1 fostered aspects of CD8⁺ T cell exhaustion, haploinsufficiency indicated that moderate Blimp-1 expression sustained some effector functions during chronic viral infection. Thus, we identify Blimp-1 as a transcriptional regulator of CD8⁺ T cell exhaustion during chronic viral infection and propose that Blimp-1 acts as a transcriptional rheostat balancing effector function and T cell exhaustion.  Finally, studies on the role of a second transcription factor, T-bet, in regulating T cell exhaustion in unexpected ways will be described.  Overall, the work presented will provide an overview of T cell exhaustion during chronic infection, how this state of T cell differentiation differs from the differentiation pathways that occur following acute infection and will describe some of the transcription pathways involved in this process.