CD8 T cell differentiation and activation disentangled - implications for autoimmune diseases and T cell memory

Effective CD8 T cell responses to acute infections consist of two components – 1) killing of infected host cells, and 2) the formation of long-lived CD8 T cell memory.

Killing of infected cells occurs during the effector phase of the response when the pathogen-specific CD8 T cell population is highly activated and on average highly differentiated (which is required for effector function).

After pathogen clearance, most pathogen-specific CD8 T cells die, but some survive as long-lived memory T cells, which are resting and on average minimally differentiated.

While CD8 T cell activation and differentiation state correlate at population level and are considered to be tightly linked, our preliminary data analyzing CD8 T cell responses to viral infection at the single-cell level show that CD8 T cell differentiation and activation status reflect distinct axes of CD8 T cell diversification.

In this project, we will 1) identify molecular markers that stratify CD8 T cells by their differentiation and activation state, 2) identify molecular regulators of CD8 T cell differentiation vs. activation state, and 3) determine the origin of memory CD8 T cells.

We will use single-cell RNA sequencing, high parameter flow cytometry and single-cell lineage tracing by cellular barcoding.

Our study has implications for autoimmune diseases where one wishes to selectively isolate or target activated CD8 T cells without affecting differentiated CD8 T cells of non-pathogenic specificities.