Show simple item record

dc.contributor.advisorMobin Karimi
dc.contributor.authorHarris, Rebecca
dc.date.accessioned2021-08-06T17:41:41Z
dc.date.available2021-08-06T17:41:41Z
dc.date.issued2021
dc.identifier.urihttp://hdl.handle.net/20.500.12648/2042
dc.description.abstractAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment used for patients with cancer or other hematological malignancies. However, widespread use of this treatment is hindered by development of graft-versus-host disease (GVHD), a life-threatening complication of allo-HSCT. Mature donor T cells in the graft mediate GVHD, but also help kill residual malignant cells in the patient by the graft-versus-leukemia (GVL) effect. Depletion of mature T cells from the graft eliminates this beneficial anti-tumor response. Mature T cells are also needed for proper stem cell engraftment. Therefore, current work has focused on how to modulate T cell signaling and function to separate GVHD from GVL. T Cell Factor-1 (TCF-1) is a T cell developmental transcription factor that is also important in some contexts for T cell activation. The role of TCF-1 in alloactivated mature T cells is completely unknown. To examine the role of TCF-1 in this context, a mouse model of allo-HSCT leading to GVHD/GVL was used to study T cells from mice with a T cell-specific deletion of TCF-1. This work showed that loss of TCF-1 separates GVHD from GVL, with reduced disease severity and persistence yet maintained GVL effects. TCF-1 affects alloactivated T cell phenotypes and suppressive profiles, as well as the major T cell functions (proliferation, migration, and cytokine/cytotoxic mediator production). TCF-1 also controls alloactivated T cell survival, apoptosis, and gene expression programs. The regulation of these functions and programs by TCF-1 is distinct in CD4 versus CD8 T cells. TCF-1 also controls two unique T cell subsets - stem-like CXCR5+ CD8+ T cells, and CD25- noncanonical Tregs. Therefore, TCF-1, or these two unique T cell types, may be a therapeutic target to improve allo-HSCT outcomes by separating GVHD from GVL effects. Expansion of CD25- Tregs during TCF-1 deficiency may also be useful for treatment of other T cell-mediated disorders as well.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectT Cell Factor-1
dc.subjectTCF-1
dc.subjectT cells
dc.subjectGVHD
dc.subjectGVL
dc.subjectimmunotherapy
dc.subjectcancer
dc.titleT Cell Factor-1 (TCF-1) Regulates Mature Alloactivated T Cells to Separate GVHD From GVL
dc.typeDissertation
refterms.dateFOA2021-08-06T18:30:20Z
dc.description.institutionUpstate Medical University
dc.description.departmentMicrobiology & Immunology
dc.description.degreelevelPhD


Files in this item

Thumbnail
Name:
2021_07-30_harris_r_dissertati ...
Embargo:
2022-07-30
Size:
20.39Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International