Dynamic regulation of T cell priming in cancer and infection
- Author(s): Hiam, Kamir J
- Advisor(s): Lanier, Lewis L
- et al.
An immunological challenge initiates cascades of migration, activation, and interactions between diverse immune cell subsets that ultimately lead to protection of the host. Previous technological limitations have favored reductionist experimentation and hindered experimental and analytical assessment of the full breadth of immunological responses. Therefore, many emergent properties of pan-lineage dynamic immune responses have remained elusive. The present body of work addresses this gap in fundamental immunology by leveraging high-dimensional single-cell technologies and in vivo mouse models of immune responses to dissect the dynamic regulation of T cell priming in both cancer and infection. Generation of immune organization maps in eight tumor models showed that the global immune macroenvironment in cancer is significantly dysregulated as shown by gross alterations in cell frequencies and phenotypes. Orthogonal pathogen challenges in tumor-burdened mice revealed peripheral defects in CD8 T cell differentiation that were caused by impaired dendritic cell (DC) activation. To further profile natural immunity to bacterial challenges, mass cytometry was adapted to profile metabolic enzymes during an in vivo bacterial immune response. We revealed a highly transient early activated CD8 T cell state characterized by peak utilization of oxidative phosphorylation and glycolysis. Assessing all splenic immune lineages during an antibacterial immune response uncovered a DC activation zenith at two days post-infection. Peak DC activation functioned as a temporal regulator of T cell fate as late arriving T cells acquired memory T cell fate exclusively. Taken together these studies reveal transient functionally significant stages of regulation during cancer and infection.