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LYMPHOCYTE TRAFFICKING, HOMING AND FUNCTION: INSIGHTS INTO THE IN VIVO BEHAVIOR OF REGULATORY T AND NATURAL KILLER CELLS

Tong, Alexander Andrew
http://rave.ohiolink.edu/etdc/view?acc_num=case1499374450217703

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, Pathology.
The immune system exists as an elaborate network of organized tissue and mobile cellular elements working in concert to defend the host against foreign pathogens and self-derived cancer cells. At the core of how the immune system works is the complex choreography of mobile immune cells actively finding their way into and out of tissues in order to exert their function. As we enter the era of immunotherapy, understanding the fundamental processes of how lymphocytes in concert with antigen presenting cells dynamically and efficiently patrol the comparatively vast body of the host is critical for discovering how to meaningfully perturb their behavior for clinical gain in cancer, infection, and autoimmune disease. Here, we study the trafficking and homing of two important lymphocyte populations: regulatory T cells (Tregs) and natural killer (NK) cells. We first describe the unique trafficking and transit properties of Tregs in peripheral lymph nodes, comparing their behavior to that of conventional T cells. Previous work has shown differences between the CD4+ and CD8+ conventional T cell subsets in terms of LN trafficking times and dendritic cell (DC) contact. We have now demonstrated using classic immunologic tools that a “resident” subpopulation of Tregs has an especially prolonged LN dwell time with concomitantly poor LN homing kinetics. Utilizing a novel imaging platform allowing first-in-kind intravital 2-photon laser scanning microscopy (2PLSM) of gut secondary lymphoid organs, we also find increased resident Treg contact with DC in mesenteric as well as other peripheral LN. Second, we study the homing and efficacy of ex vivo-expanded NK (eNK) cells for the therapy of metastatic Ewing’s sarcoma (ES). We observe that eNK cells have a strong lung, spleen, and liver homing tropism and are able to significantly reduce pulmonary metastases of ES. While this is incredibly promising for clinical purposes, eNKs are ultimately unable to penetrate the primary tumor site, likely due to a lack of appropriate homing receptors and cues. These data underscore the pressing need to uncover mechanisms by which we might be able to drive desired lymphocyte populations into the tumor microenvironment. As we investigate and understand more about why certain lymphocyte populations reside in or quickly transit through different tissues, we hope the knowledge gained will help lead to more effective cellular immunotherapies in cancer and other diseases.
Alex Huang, MD, PhD (Advisor)
Robert Fairchild, PhD (Committee Chair)
George Dubyak, PhD (Committee Member)
Clive Hamlin, PhD (Committee Member)
Booki Min, DVM, PhD (Committee Member)
Immunology

Recommended Citations

Citations

  • Tong, A. A. (n.d.). LYMPHOCYTE TRAFFICKING, HOMING AND FUNCTION: INSIGHTS INTO THE IN VIVO BEHAVIOR OF REGULATORY T AND NATURAL KILLER CELLS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1499374450217703

    APA Style (7th edition)

  • Tong, Alexander. LYMPHOCYTE TRAFFICKING, HOMING AND FUNCTION: INSIGHTS INTO THE IN VIVO BEHAVIOR OF REGULATORY T AND NATURAL KILLER CELLS. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1499374450217703.

    MLA Style (8th edition)

  • Tong, Alexander. "LYMPHOCYTE TRAFFICKING, HOMING AND FUNCTION: INSIGHTS INTO THE IN VIVO BEHAVIOR OF REGULATORY T AND NATURAL KILLER CELLS." Doctoral dissertation, Case Western Reserve University. Accessed APRIL 25, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1499374450217703

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.