Regulation and therapeutic targeting of virus-specific resident memory T cells

Author

Jordan Fredriksen IsaacsFollow

Date of Award

Spring 4-19-2024

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Pamela Rosato

Abstract

CD8+ T cells are critical to the immune response to pathogens, as they kill infected cells and generate immunologic memory. Following infection, antigen-specific T cells expand approximately 10,000-fold and migrate to sites of inflammation in order to clear the pathogen. Once infection is resolved, a small pool of memory T cells persist in circulation and within tissues ready to respond rapidly upon re-exposure. Given the importance of CD8+ T cells, significant efforts have been made over the years to better understand how different memory T cell subsets are established, maintained, and regulated. The most recently identified subset, resident memory T cells (T_RM), are of particular interest to our laboratory and have powerful inflammatory functions that can be leveraged as therapies. Tumors are comprised of a heterogeneous T cell compartment, including T_RM with specificity for tumor and viral antigens. While many immunotherapies aim to reinvigorate tumor-specific T_RM, our laboratory focuses on the therapeutic potential of these ‘bystander,’ or ‘cancer-unrelated’ T cells. Further, tumor-specific T cells have been proposed to express CD39, an exhaustion marker expressed on T cells responding to chronic viral infections. However, we have identified that CD39 and its co-ectoenzyme, CD73, are differentially expressed on precursor cells and co-expressed on T_RM following an acute viral infection, suggesting a novel role for CD39 in T cell differentiation. Therefore, this thesis expands our understanding of virus-specific T_RM reactivation in additional tumor types and characterizes the unique expression of purinergic ecto-enzymes during the anti-viral T cell response.

Original Citation

CD39 is expressed on functional effector and tissue resident memory CD8+ T cells Jordan F. Isaacs, Hanna N. Degefu, Tiffany Chen, Sierra A. Kleist, Shawn C. Musial, Myles A. Ford, Tyler G. Searles, Chun-Chieh Lin, Alexander G. J. Skorput, Keisuke Shirai, Mary Jo Turk, George J. Zanazzi, Pamela C. Rosato bioRxiv 2024.03.15.585252; doi: https://doi.org/10.1101/2024.03.15.585252

Recommended Citation

Isaacs, Jordan Fredriksen, "Regulation and therapeutic targeting of virus-specific resident memory T cells" (2024). Dartmouth College Ph.D Dissertations. 272.
https://digitalcommons.dartmouth.edu/dissertations/272