Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion

Chronic infection with persistent antigenic stimulation results in the generation of exhausted CD8(+) T cells, which are considered defective effector CD8(+) T cells, and thus compromises effective immune responses. However, recent studies have illustrated that exhausted CD8(+) T cells may be purposely generated and maintained to provide mild immune responses against chronic infection or cancer, which can be safer over a long period of time than strong immune responses. Indeed, a specific population of exhausted CD8(+) T cells that behaves similarly to self-renewing stem cells and provides a continuous supply of exhausted CD8(+) T cells has been identified, indicating that this population can be considered progenitors of exhausted CD8(+) T cells. Furthermore, several ground-breaking studies in the last few years have shed new light on the transcriptional regulatory network governing the generation and propagation of exhausted CD8(+) T cells, which involves T cell receptor (TCR) signaling that leads to NFAT-TCF1 (nuclear factor of activated T cells-T cell factor 1) activity followed by activation of the TOX/NR4A axis. Elucidation of the intracellular signaling pathways will help to define the definitive developmental stages leading to exhausted CD8(+) T cells, which can be exploited to advance our never-ending battle against cancer. This review will summarize the recent discoveries that have deepened our understanding of the exhaustion program of cytotoxic CD8(+) T cells. Immunity: exhausted T cells provide subtle long-term defenses A type of T cell previously thought to be defective could actually provide long-term mild immune responses for combating cancer. The unique environment created during chronic infections gives rise to functionally inert T cells known as 'exhausted' cells, which were once thought to impede immune responses. Wooseok Seo and co-workers at Nagoya University and the National Cancer Center in Tokyo, Japan, have reviewed recent studies suggesting that exhausted T cells may be generated by the body to provide mild immune responses. Such responses are safer over the long term than strong inflammatory defense mechanisms, where T cells may be overstimulated, leading to uncontrolled tissue damage and induced T cell death. The signaling pathways that generate and propagate exhausted cells are being revealed, shedding light on the developmental stages that lead to this subtle but effective response to chronic conditions.

Automated summary

Exhausted CD8(+) T cells may be deliberately generated and maintained to provide mild immune responses against chronic infection or cancer, which can be safer over the long term compared to strong immune responses. A specific population of exhausted CD8(+) T cells that behaves like self-renewing stem cells has been identified, suggesting they can be considered progenitors of exhausted CD8(+) T cells. Studies have revealed the regulatory network governing the generation and propagation of exhausted CD8(+) T cells, shedding light on the developmental stages that lead to this subtle but effective immune response.