ICOS limits memory-like properties and function of exhausted PD-1 CD8 T cells.

During persistent antigen stimulation, PD-1 CD8 T cells are maintained by progenitor exhausted PD-1 TCF-1 CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1 CD8 T cell responses has not been addressed.

Universal recording of immune cell interactions in vivo.

Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function. To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts), an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4 T helper cells and antigen-presenting cells, however.

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 PD-1 CD8 T cells.

During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection.

Advancing beyond the twists and turns of T cell exhaustion in cancer.

Chronic antigen stimulation leads to T cell exhaustion. Nutrient restrictions and other suppressive factors in the tumor microenvironment further exacerbate T cell dysfunction. Better understanding of heterogeneity and dynamics of exhausted CD8 T cells will guide novel therapies that modulate T cell differentiation to achieve more effective antitumor responses.