T cell exhaustion was described more than a decade ago as dysfunction and subsequent physical deletion of antigen-specific T cells during chronic viral infection in mice. Since then, T cell exhaustion has been demonstrated in a wide variety of animal models and in humans with chronic viral, bacterial and parasitic infections as well as during human cancer. Although the details of T cell dysfunction differ for specific pathogens, a general phenotypic and functional portrait of T cell exhaustion is becoming clearer. Recently, two emerging themes have shed considerable light on the understanding of T cell exhaustion. The first is the understanding that both extrinsic negative regulatory pathways (such as immunoregulatory cytokines) and cellintrinsic negative regulatory pathways (such as PD-1) have key roles in exhaustion. Second, an accurate molecular definition of exhaustion is unfolding. These studies suggest that exhausted T cells represent a distinct state of T cell differentiation and that more comprehensive molecular analyses of T cell exhaustion in different settings may identify common underlying principles and clinical opportunities.

Although functional effector T cells can transiently express inhibitory receptors during activation, prolonged and/or high expression of multiple inhibitory receptors is a key feature of the exhaustion of CD8+ and CD4+ T cells both in animal models and in humans. The axis of PD-1 and its ligand seems to be a major inhibitory receptor pathway involved in T cell exhaustion, and blocking this pathway during chronic LCMV infection reinvigorates virus-specific CD8+T cell responses and results in a lower viral load. Virus-specific CD8+ T cells during chronic infection in animal models and in humans can also coexpress LAG-3, CD244 (2B4), CD160, TIM-3, CTLA-4 and many other inhibitory receptors. Understanding the downstream mechanisms of these diverse inhibitory receptors is a major goal.

Soon after studies first described T cell exhaustion in mice, it became apparent that similar kinds of CD8+ T cell dysfunction exist in humans. For example, HIV-, HCV- and HBV-specific CD8+ T cells that partially or, in some cases, fully lack ex vivo effector function have been identified. As in mice, high viral load and low CD4+ T cell help is correlated with more severe exhaustion, although the precise features of exhaustion vary during different infections.

A central question - whether exhaustion can be fully reversed, leading to highly functional, antigen-independent, long-lived T cell memory - remains unanswered. The answer is probably related to the lineage relationships among exhausted, effector and memory T cells and also the population dynamics after reinvigoration of exhausted T cell responses. An additional key question is whether the increasing understanding of T cell exhaustion at the molecular and global transcriptional levels can be used to inform prophylactic vaccination strategies. For example, the transcriptional signature of an exhausted T cell should probably be avoided in the profiles of vaccineinduced T cells aimed at protection from HIV, HCV and other persisting pathogens. It will be useful to determine how information about T cell exhaustion can be integrated into the development therapeutic and prophylactic vaccination strategies for these diseases.