Pinpointing molecular regulators of CD8 T cell differentiation through multimodal single-cell profiling

Abstract

Abstract CD8 T lymphocytes control infection and malignancy through differentiation into specialized cell states with discrete functional attributes. While CD8 T cell fate commitment is a transcriptionally and epigenetically controlled process, the transcription factors and chromatin modifiers governing CD8 T cell differentiation remain ill-defined. Here, we leveraged mouse models of viral infection and cancer to simultaneous profile the chromatin and transcriptomic landscapes of virus-specific and tumor-specific CD8 T cells at single-cell resolution. Through in-depth comparison of antigen-specific CD8 T cells across distinct disease settings, we define uncharacterized CD8 T cell states and clarify roles for molecular regulators of T cell heterogeneity. Comparison of uniquely accessible regions of chromatin along with predicted transcription factor activity uncover regulatory networks that both guide and enforce CD8 T cell fate commitment into novel and established states spanning T cell memory, residency, and exhaustion. Further, we have functionally defined novel roles for several transcriptional regulators in controlling CD8 T differentiation during infection and cancer, including undescribed roles for the transcription factor Runx3. Together, our findings clarify CD8 T cell heterogeneity and differentiation trajectories across acute infection, chronic infection, and cancer. We show our findings can be leveraged to enhance promising immunotherapy approaches. AAI Intersect Fellowship Program for Computational Scientists and Immunologists (2022-2023)