We previously found that fetal-derived CD8+ T cells are the first to respond to acute infection in adulthood but rapidly become short-lived effectors. In contrast, adult-derived CD8+ T cells respond with slower kinetics but give rise to more memory CD8+ T cells. An important question is why, but we lack critical information on how developmental origins alter CD8+ T cell position and behavior during priming in the lymph node. To overcome this challenge, we have formed a collaboration with Chris Xu’s lab to combine fate-mapping ‘timestamp’ mice with high-resolution three-photon (3P) microscopy to image the behavior of live T cells throughout the entire depth of the lymph node during infection. Upon completion of these studies, we expect to provide a new conceptual framework to explain why individual CD8+ T cells behave in distinct ways in the lymph node and are recruited into the response with different kinetics.
Why are fetal-derived CD8+ T cells the first to respond to adult infection?
What is a marker for fetal-derived CD8+ T cells?
Our previous work indicates that there are separate lineages of CD8+ T cells (fetal-derived and adult-derived) in the starting population, which are made during distinct windows of development and differentiate along different pathways during infection. However, we lack a useful marker to distinguish fetal- and adult-derived CD8+ T cells in adult mice, and we still do not fully understand the underlying basis for their altered behavior. Based on our preliminary data, we have identified a scavenger receptor (CD163L1) that is specifically expressed on fetal-derived CD8+ T cells and potentially contributes to their more rapid innate-like functions. Thus, we are developing tools to establish whether CD163L1 is a bona fide marker for fetal-derived CD8+ T cells, and whether it contributes to the altered functions of fetal-derived CD8+ T cells. This work has the potential to open up new avenues of research and advance our conceptual understanding of the CD8+ T cell response to infection.
How does developmental origin alter the CD8+ T cell response to persistent and chronic pathogens?
Our past work demonstrated that the fate of CD8+ T cells during infection is linked to the developmental origin of the responding cells. However, this work was performed in the context of acute infection. Thus, we are currently examining how fetal- and adult-derived CD8+ T cells respond to persistent (HSV1, CMV) and chronic (LCMV) viral pathogens. We are specifically interested in learning whether fetal-derived CD8+ T cells have an inherent propensity to undergo memory inflation during persistent viral infection or whether they become exhausted during chronic infection. To address these questions, we are working closely with Miles Davenport’s lab to use mathematical modeling to dissect out the heterogeneity in the CD8+ T response to persistent and chronic pathogens. The results obtained will aid in the development of more precise immunotherapies for infection and cancer and allow us to predict how individuals will respond to treatment.
We recently demonstrated that fetal-derived CD8+ T cells represent a distinct lineage of lymphocytes that are derived from Lin28b progenitors and possess innate-like qualities. Unlike adult-derived CD8+T cells, fetal-derived CD8+ T cells can be activated by cytokines alone and protect the host against a wide range of pathogens (viruses, bacteria, worms) in the absence of T-cell receptor (TCR) signaling. Now, the question is, what are the epigenetic and transcriptional mechanisms that enable neonatal CD8+ T cells to be more responsive to innate cytokines? Also, what are the key transcription factors that specify either innate or adaptive functions in CD8+ T cells, and how does the fetal thymus program CD8+ T cells for innate defense? To answer these questions, we are collaborating with Andrew Grimson’s lab and using a variety of molecular (single cell RNA-seq, ATAC-seq) and experimental approaches (thymic transplants, artificial thymic organoids, thymic injections) to uncover the developmental pathway of fetal-derived CD8+ T cells.