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Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells

Meibers, Hannah
http://orcid.org/0000-0002-5084-5701
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703170207776797

Abstract Details

2023, PhD, University of Cincinnati, Medicine: Immunology.
Cognate interaction between effector memory CD4+ T cells (TEM) and dendritic cells (DCs) induces innate inflammatory cytokine production, resulting in detrimental outcomes such as autoimmune pathology and cytokine storms. We previously established that TEM cells use TNF superfamily ligands to activate DCs, yet whether this interaction with DCs induces other cell intrinsic changes that influence inflammatory responses by DCs has never been investigated. Here we have made a surprising discovery that TEM cells trigger double-strand DNA breaks via mitochondrial ROS production in interacting DCs. Initiation of the DNA damage response in DCs leads to activation of a cGAS-independent, non-canonical STING-TRAF6-NFκB signaling axis. Consequently, STING deficient DCs display reduced NFκB activation leading to significant defects in transcriptional induction and functional production of IL-1β and IL-6 following their interaction with TEM cells, both in vitro and in vivo. The discovery of TEM cell-induced innate inflammation through DNA damage and a non-canonical STING-NFκB pathway presents this pathway as a potential target to alleviate T cell driven inflammation in autoimmunity and cytokine storms.
Chandrashekhar Pasare, Ph.D. (Committee Chair)
Jonathan Katz, Ph.D. (Committee Member)
Sing Sing Way, M.D. Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
Daniel Starczynowski, Ph.D. (Committee Member)
Leah Claire Kottyan, Ph.D. (Committee Member)
169 p.
Immunology
non-canonical STING; DNA damage response; TRAF6; ROS; CD4 memory T cells; dendritic cells

Recommended Citations

Citations

  • Meibers, H. (2023). Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703170207776797

    APA Style (7th edition)

  • Meibers, Hannah. Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells. 2023. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703170207776797.

    MLA Style (8th edition)

  • Meibers, Hannah. "Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells." Doctoral dissertation, University of Cincinnati, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703170207776797

    Chicago Manual of Style (17th edition)

ucin1703170207776797
48
© 2023, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.