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Dissertation
Dynamics of dendritic cells and T cells in HTLV-1 associated oncogenesis and neuroimflammation: implications in immunomodulatory therapies and diagnostic tools
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2011
DOI:
https://doi.org/10.17918/00008803
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of two immunologically distinct diseases: adult T-cell leukemia (ATL) and HTLV-1associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although HTLV-1-specific CD8+ cytotoxic T cells (CTL) response is seen in both pathogenic states but its actual significance in preventing viral load and controlling disease progression remained questionable. The proper functionality of a CTL response relies on several factors including the efficiency of epitope processing and presentation. In this respect, dendritic cells (DCs), have long been recognized as key regulators of the immune system. In studies presented herein we closely examined in vitro and in vivo priming of naive CD8+ T cells through DC-mediated presentation of HTLV antigens such as its transactivator protein Tax. We observed both HTLV-1 and Tax not only can mature DCs, but can also can induce a Tax-specific response. Similar observations were made during the in vivo studies utilizing syngeneic DCs from Tax immunized HLA-A*0201 transgenic mice, indicating that DCs are most likely the major Tax presenting cell during HTLV-1 infection. We then extended these observations to an ex vivo system, utilizing peripheral blood mononuclear cells of 4 clinical groups from Jamaica: seronegative controls, asymptomatic carriers (ACs), ATL, and HAM/TSP. Extensive immune profiling revealed that CTLs from both HAM/TSP and ATL patient samples demonstrated some functional responses, albeit to a much lesser extent than those responses seen in ACs. Moreover, DCs from HTLV-1-diseased individuals exhibited an altered maturation and adhesion phenotype as compared to ACs. The expression of two inhibitory molecules PD-1 and PD-L1 was upregulated in CTLs and DCs, respectively in both diseased groups. While comparing the matched proviral loads to the flow cytometry results, we identified unique immune signatures distinguishing ACs from ATL and HAM/TSP patients. Collectively, these results demonstrate the critical role of DCs in their ability to prime immune responses and highlight a significant aspect of viral immunopathogenesis related to the development of ATL and HAM/TSP. Furthermore, these results suggest that cellular modulation and/or blockade of the PD-1/PD-L1 pathway may be useful in therapeutic interventions for ATL and/or HAM/TSP.
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Details
- Title
- Dynamics of dendritic cells and T cells in HTLV-1 associated oncogenesis and neuroimflammation
- Creators
- Sharrón L. Manuel
- Contributors
- Pooja Jain (Advisor) - Drexel University, Drexel University (1970-)Brian Wigdahl (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xxi, 296 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021888975004721