Exhausted T cells have been shown to be a heterogeneous population consisting of distinct T cell subsets with differing residual functions. Therapeutic antibody blockade of inhibitory pathways and factors can amplify T cell function, yet the mechanisms by which this therapy reshapes T cell responses, and the specific T cell subsets that it targets remain ill defined. We conducted single cell proteomic and transcriptomic studies to identify the CD4 and CD8 T cell subsets, in conjunction with other immune cell types, that are amplified during chronic inflammation and altered upon anti-PDL1 immunotherapy. This talk will discuss these responsive T cell subsets and the molecular pathways and identifying biomarkers that are induced upon anti-PDL1 therapy. I will additionally discuss how the immune environment during chronic infection alters de novo T cell induction and sets the stage for their contribution to viral control.