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A Critical Role for Gimap5 in CD4+ T Cell Homeostasis and Maintenance of Peripheral Immune Tolerance

Aksoylar, Halil I
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367937122

Abstract Details

, PhD, University of Cincinnati, Medicine: Immunology.
T cell lymphopenia is a condition which arises from defects in T cell development and/or peripheral homeostatic mechanisms. Importantly, lymphopenia is often associated with T cell-mediated pathology in animal models and in patients with autoimmune disease. In this thesis, using an ENU mutagenesis approach, we identified sphinx mice which presented severe lymphopenia due to a missense mutation in Gimap5. Characterization of Gimap5sph/sph mice revealed that Gimap5 is necessary for the development of NK and CD8+ T cells, and is required for the maintenance of peripheral CD4+ T and B cell populations. Moreover, Gimap5-deficient mice developed spontaneous colitis which resulted in early mortality.Gimap5sph/sph CD4+ T cells presented progressive lymphopenia-induced proliferation (LIP), became Th1/Th17 polarized, and mediated the development of colitis. Furthermore, Gimap5sph/sph FoxP3+ regulatory T cells became selectively reduced in the mesenteric lymph nodes and adoptive transfer of wild type regulatory T cells prevented colitis in Gimap5-deficient mice. Importantly, the expression of Foxo transcription factors, which play a critical role in T quiescence and Treg function, was progressively lost in the absence of Gimap5 suggesting a link between Gimap5 deficiency and loss of immunological tolerance. Using OT-II RAG-/- TCR transgenic model, we showed that treatment with cognate antigen under tolerizing conditions failed to induce a Treg population and resulted in the acquisition of LIP phenotype by Gimap5-deficient CD4+ T cells. Given that Gimap5 is expressed in lysosomes, we investigated whether Gimap5 is involved in lysosomal-autophagosomal pathways. Upon TCR activation, we observed larger autophagosomes that colocalize with mitochondria in Gimap5sph/sph CD4+ T cells suggesting an abnormal rate of mitochondrial turnover. Furthermore, TCR activated Gimap5sph/sph CD4+ T cells displayed elevated levels of reactive oxygen species (ROS) and oxygen consumption rate (OCR) indicating defects in mitochondrial function. Our results establish the critical role of Gimap5 in CD4+ T cell homeostasis and maintenance of peripheral tolerance. Importantly, our results provide a basis for further investigation of the molecular mechanisms how Gimap5 is involved in T cell homeostasis.
Kasper Hoebe, Ph.D. (Committee Chair)
Julio Aliberti, Ph.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
Christopher Karp, M.D. (Committee Member)
David Plas, Ph.D. (Committee Member)
241 p.
Immunology
Giamp5; Lymphopenia; CD4 T cells; T cell homeostasis; Colitis; Autoimmunity;

Recommended Citations

Citations

  • Aksoylar, H. I. (n.d.). A Critical Role for Gimap5 in CD4+ T Cell Homeostasis and Maintenance of Peripheral Immune Tolerance [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367937122

    APA Style (7th edition)

  • Aksoylar, Halil. A Critical Role for Gimap5 in CD4+ T Cell Homeostasis and Maintenance of Peripheral Immune Tolerance. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367937122.

    MLA Style (8th edition)

  • Aksoylar, Halil. "A Critical Role for Gimap5 in CD4+ T Cell Homeostasis and Maintenance of Peripheral Immune Tolerance." Doctoral dissertation, University of Cincinnati. Accessed APRIL 18, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367937122

    Chicago Manual of Style (17th edition)

ucin1367937122
552
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