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Human Innate Lymphoid Cell Biology and Development

Chen, Luxi
http://orcid.org/0000-0002-8880-3347
http://rave.ohiolink.edu/etdc/view?acc_num=osu1551901769401192

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Studies of human lymphopoiesis are important towards gaining a thorough understanding of normal immune cells and can provide insights into the pathophysiology of immune disorders and deficiencies. Innate lymphoid cells (ILCs) are a newly discovered family of immune cells with emerging roles in the defense against cancer, viral and bacterial infections, allergies, and autoimmune diseases. These immune cells are unique in that they share features of both innate and adaptive immunity. While ILCs lack the ability to respond in an antigen-specific manner, they closely resemble adaptive lymphocytes in terms of transcriptional signatures and effector function. There are four types of ILCs: cytotoxic natural killer (NK) cells and as many as three subsets of non-cytotoxic, cytokine-producing “helper” ILCs termed ILC1s, ILC2s, and ILC3s (the existence of ILC1s in states of normal human physiology remains controversial). Currently, little is known about the development and regulation of helper ILCs. Previously, our laboratory discovered a comprehensive pathway of human NK cell development in secondary lymphoid tissues (SLTs) such as tonsils and lymph nodes exclusive of other ILCs, and have begun to explore human ILC development in general. In particular, we and others have described and characterized multipotent CD34+CD117- progenitor cells as well as CD34+CD117+ common ILC progenitors in human tonsils. Based on these data, we hypothesized that in humans all ILCs share a common developmental pathway in tonsils and that at some point, each ILC subset terminally differentiates along its own developmental trajectory. Here we elucidated key steps of NK cell, ILC2, and ILC3 development within human tonsils using ex vivo molecular, transcriptional, and functional profiling and lineage differentiation assays. We demonstrated that while tonsillar NK cells, ILC2s, and ILC3s originate from a common ILC precursor cell identified as CD34-CD117+, final steps of ILC2 development deviate independently and become mutually exclusive from those of NK cells and ILC3s, whose developmental pathways overlap. Moreover, we discovered a CD34-CD117+ ILC precursor population that expresses CD56 and gives rise to NK cells and ILC3s but not to ILC2s. Collectively, our data support a comprehensive model for human ILC development in tonsils, advancing our understanding of basic ILC biology within the human immune system. Importantly, elucidating these fundamental developmental pathways have enabled us to gain greater insight into how cancer cells can disrupt ILC development and function to further disease progression.
Michael Caligiuri, M.D. (Advisor)
Aharon Freud, M.D., Ph.D. (Advisor)
Don Benson, M.D., Ph.D. (Committee Member)
Susheela Tridandapani, Ph.D. (Committee Member)
155 p.
Biomedical Research; Immunology
Human innate lymphoid cells; ILC development; natural killer cells; cancer

Recommended Citations

Citations

  • Chen, L. (2019). Human Innate Lymphoid Cell Biology and Development [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1551901769401192

    APA Style (7th edition)

  • Chen, Luxi. Human Innate Lymphoid Cell Biology and Development. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1551901769401192.

    MLA Style (8th edition)

  • Chen, Luxi. "Human Innate Lymphoid Cell Biology and Development." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1551901769401192

    Chicago Manual of Style (17th edition)

osu1551901769401192
383
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This open access ETD is published by The Ohio State University and OhioLINK.