CD8 T cells form the central component of the adaptive immune system and are essential in defense against viral and bacterial infections and in tumor immunity. Better molecular characterization of CD8 T cells in different contexts is fundamentally important and can lead to improved clinical results in cancer immunotherapies, infectious diseases, autoimmunity. We performed an extensive genomic, single-cell, and transcription factor analysis of CD8 T cell functional and dysfunctional states. We now continue studying regulatory mechanisms and cell-cell interactions governing CD8 T cell activation and functional commitment across immune challenges in mouse and human using single-cell and spatial multi-omics. We are also expanding these approaches to other immune cell types.