Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections

CD8 T cell differentiation is a tightly regulated process generating effector and memory T cells over the course of acute infections. In cancer and chronic infection, this differentiation program is derailed, and antigen-specific CD8 T cells differentiate to a hyporesponsive state generally referred to as T cell exhaustion. Here, we review recent findings on heterogeneity of tumor-specific T cells and exhausted T cells during chronic infections, discussing distinct differentiation state dynamics, fate choices, and functional states. Delineating the regulatory mechanisms defining distinct T cell states and determining the requirements for therapeutic reprogramming of these states will provide needed insights for the design of effective immunotherapies for the treatment of cancer and chronic infections.