Figure 3.

Model of T_EX heterogeneity and key markers linked to individual subsets. Within the pool of exhausted T cells, three major trajectories of T_EX subsets are proposed. Early T_EX can give rise to a pool of disease-associated or health-associated T_EX that massively differ in their activation program as well as in their transcriptional signature, while between both extremes, a balanced pool of differentiated T_EX can be observed. One differentiation trajectory leads to populations with high homeostatic potential that are identified in settings of disease control (“health-associated T_EX”) and can have memory-like features, such as high TCF-1 and CD127 expression. Strong expression of activation markers also found on T_EFF cells (e.g., CD38, CD39) and co-expression of many inhibitory receptors (IRs) is a key feature of T_EX populations identified in progressive disease in chronic infection and cancer. According to this model, T_EX with recent history of activation and severe exhaustion after priming express a different set of IRs (e.g., PD-1, CTLA-4, Lag-3) more frequently observed in cancer compared to highly activated T cells arising in many chronic infections. These highly activated T cells in chronic infection are thought to arise from an intermediate trajectory of T_EX (expressing e.g., PD-1, 2B4, TIGIT) after encountering additional antigen stimulation and inhibitory signals. Furthermore, a precursor-progenitor relationship between health- and disease-associated T_EX important for cancer immunotherapy has been described, and is indicated by the dotted lines. The different T_EX trajectories also reflect differential transcriptional programming by varying T-bet, TCF-1, TOX and Eomes expression.