Azad Rahimpour (2010). ROLE OF DENDRITIC EPIDERMAL T-CELLS IN SKIN GRAFT REJECTION PhD Thesis, Diamantina Institute for Cancer, Immunology and Metabolic Medicine, The University of Queensland.

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Author Azad Rahimpour
School, Centre or Institute Diamantina Institute for Cancer, Immunology and Metabolic Medicine
Institution The University of Queensland
Publication date 2010-02
Thesis type PhD Thesis
Supervisor Prof. Ian Frazer
Dr. Graham Leggatt
Prof. Gary Halliday
Total pages 180
Total colour pages 20
Total black and white pages 160
Subjects 11 Medical and Health Sciences
Abstract/Summary γδ T cells belong to the T cell lineage however they possess some innate like properties. γδ T cells recognize non-peptidic microbial and stress induced self antigens in a non-MHC restricted manner and are proposed to bridge the gap between innate and adaptive immunity. Dendritic epidermal T cells are a prototypic population of intraepithelial γδ T cells in murine skin. Found in the basal layer of epidermis in close contact with Langerhans cells and keratinocytes DETC facilitate vital immunological and physiological processes e.g. wound healing, homeostasis, tumour surveillance and regulation of inflammation. The purpose of this thesis was to elucidate whether γδ T cells and in particular DETC play a role in generation of adaptive immune responses to foreign cutaneous antigen (OVA) in the context of skin grafts. Skin grafting has long been established as a means to test cutaneous and epithelial immunity. To answer this question, γδ T cell knock-out mice (TCRδ-/-), transgenic K5mOva mice and a skin grafting model were used. It is shown in this study that in the absence of γδ in the skin and not in the circulation there is a lower rejection rate of OVA expressing skin grafts. This phenomenon is observed in both freshly placed and well healed grafts. To understand which part of the immune response is affected by the absence of γδ T cells the priming and effector phases of the immune response was examined in TCRδ-/- mice. The priming phase was studied using two approaches: the first approach was to test priming to maximal doses of subcutaneous antigen in conjunction with an adjuvant and the second approach involved testing priming to an antigen in the context of skin grafts (graft priming). Using ELISPOTs and CFSE proliferation assays we found that while administration of OVA in conjunction with an adjuvant (QuilA) via the subcutaneous route results in sufficient priming in γδ T cell knockout mice, cross priming to OVA in the context of - freshly placed and well healed skin grafts is impaired in TCRδ-/- mice. By immunizing TCRδ-/- mice prior to skin grafting or by transferring in vitro primed OT-I cells to RAG-/- mice grafted with K5mOVA or TCRδ-/-OVA skin it was shown that 100% of all OVA grafts are rejected regardless of presence or absence of γδ T cells, concluding that effector phase of the immune response is not affected in this model. The inability of DETC to perform the role of cross presentation leads to the hypothesis that DETC indirectly enhance this process by affecting professional antigen presenting cells (APC) of the skin. Based on the contribution of DETC to wound healing it was hypothesized that the migration of dendritic cells (DCs) from the skin grafts to the lymph nodes may be affected. When this hypothesis was tested using hapten sensitization and congenically marked skin grafts it was shown that migration of DCs from skin grafts is not affected by the absence of DETC. In another hypothesis the co-stimulatory markers CD40 and CD86 were examined on migrating DCs found in the skin draining lymph nodes of grafted mice and it was shown that expression levels of those molecules were lower on DCs from TCRδ-/- grafted mice compared to C57BL/6 control mice. In addition using cytometric bead array, we show that the cytokine milieu in TCRδ-/- skin and skin draining lymph nodes is different from that of wildtype C57 skin and this disparate cytokine profile may be contributing to the less efficient cross priming and graft rejection in TCRδ-/- mice.
Keyword γδ T cells
Graft rejection
Cross Priming
Innate Immunity
Additional Notes Pages to be printed in color: 1,13,14,22,54,59,67,75,77,78,80,81,83,94,96,105,117,118,120, 134

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Created: Tue, 18 May 2010, 00:20:45 EST by Mr Azad Rahimpour on behalf of Library - Information Access Service