The process of T cell exhaustion in chronic viral infection and possible effects of ipilimumab. a) After the introduction of initial antigen (infection), naive CD8+ T cells are primed by antigen and, with concomitant stimulation and ongoing inflammation, mature into effector CD8+ T cells. As the antigen (infection) clears, a subset of the effector CD8+ T cells further differentiate into memory CD8+ T cells with the ability to produce cytokines such as IL-2, tumor necrosis factor (TNF) and interferon-γ (IFN-γ), then degranulate, proliferate and self-rejuvenate. In the event of chronic antigen exposure (infection) and subsequent increasing viral load and persistence of antigen (infection), mature effector CD8+ T cells proceed through a hierarchical process of exhaustion, loss of effector functions including the ability to produce cytokines and degranulate, the progressive expression of inhibitory receptors, and the loss of the ability to proliferate and self-rejuvenate and elimination. These processes culminate in the loss of virus-specific CD8+ T cell responses. b) Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is an inhibitory receptor expressed on the surface of exhausted CD8+ T cells. It is analogous to, but serves the opposite function of, the CD28 T cell receptor also found on the surface of these cells. Activated antigen presenting cells (APC) loaded with antigen express CD80/86, which can either bind CD28 resulting in a stimulatory signal, or bind to CTLA-4 resulting in attenuation of further intracellular signaling and gene expression and ultimately CD8+ T cell response. c) Ipilimumab is a monoclonal antibody that targets the CTLA-4 receptor on CD8+ T cells. It functions by binding the CTLA-4 receptor, thus preventing CD80/86-CTLA-4 binding and the resultant CD8+ T cell attenuation, thereby halting and potentially reversing the process of CD8+ T cell exhaustion.