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dc.contributor.advisorCao, Xuefang
dc.contributor.authorO'Neill, Rachel
dc.date.accessioned2019-10-29T16:48:36Z
dc.date.available2019-10-29T16:48:36Z
dc.date.issued2019
dc.date.submitted2019-08-28 12:39:52
dc.identifier.urihttp://hdl.handle.net/10477/80970
dc.descriptionPh.D.
dc.description.abstractAllogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for a variety of hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) remains the major complication that causes significant morbidity and mortality despite the currently practiced immunosuppressive therapies. New approaches for controlling GVHD while preserving the beneficial graft-versus-leukemia/lymphoma (GVL) effect are necessary if we hope to achieve the curative potential of allo-HCT, which requires a better understanding of the underlying mechanisms. GVHD is known to be caused by donor-derived T cells that recognize allogeneic antigens expressed on host cells and subsequently damage host normal tissue. In addition to TCR signaling stimulated by MHC-antigen complex, co-stimulatory pathways are involved in T cell activation and function. The co-stimulatory molecule CD27 is a TNF receptor family member constitutively expressed on T cells, B cells and NK cells and its ligand, CD70, is known to be expressed on activated antigen-presenting cells (APC) as well as T cells. Interaction of CD27 and CD70 in inflammatory conditions has been shown to cause immune dysregulation and immunopathology. However, the role of this pathway in an allogeneic transplantation setting is previously unknown. The CD27-CD70 pathway is known to provide a costimulatory signal with CD70 expressed on antigen-presenting cells while CD27 functioning on T cells. Although CD70 is also expressed on activated T cells, it remains unclear how T cell-derived CD70 affects T cell function. Therefore, we have assessed the role of T cell intrinsic CD70 using adoptive transfer models including autoimmune inflammatory bowel disease (IBD) and allogeneic graft-versus-host disease (GVHD). Compared with WT T cells, CD70-/- T cells xi surprisingly caused more severe IBD and GVHD and produced higher levels of inflammatory cytokines. Mechanistic analyses reveal that IFN- induces CD70 expression in T cells, and CD70 limits T cell expansion via a regulatory T cell-independent mechanism that involves caspase-dependent T cell apoptosis and upregulation of inhibitory immune checkpoint molecules. Overall, our findings demonstrate for the first time that T cell-derived CD70 plays a novel immune checkpoint role in inhibiting inflammatory T cell responses. This study suggests that T cell-derived CD70 performs a critical negative feedback function to downregulate inflammatory T cell responses. Following lethal irradiation, emergency hematopoiesis of stem cells occurs in the bone marrow niches. Triggering of host-derived CD27 on hematopoietic stem cells then skews differentiation towards an anti-inflammatory cell phenotype. Hostderived CD27 inhibits GVHD as CD27-/- hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased clinical GVHD score. In addition, CD27-/- hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD27-/- versus wild-type hosts. Mechanistic analyses suggest that CD27 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Overall, our findings demonstrate that host CD27 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.
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dc.language.isoen
dc.publisherState University of New York at Buffalo
dc.rightsUsers of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.
dc.subjectImmunology
dc.titleEssential Role of CD27/CD70 pathway in inflammatory T cell response
dc.typeDissertation
dc.rights.holderCopyright retained by author.


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