Drexel University College of Medicine

M.D./Ph.D. Program Microbiology and Immunology Graduate Program B.S., Biomedical Engineering, Drexel University Email: slk23@drexel.edu Advisor: Dr. Pooja Jain

Thesis Research Summary:

Dendritic cells are the most potent antigen presenting cells and are key regulators of the immune system, linking both stimulatory and inhibitory components of normal immunity. While dendritic cells are well characterized with respect to primary and secondary immune responses in many viral infections, their unique role in human T cell leukemia virus type 1 (HTLV-1) pathogenesis has not been fully delineated.  HTLV-1 is the etiologic agent of several pathologic outcomes, one of which we focus on: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).  HAM/TSP is an incurable, chronic debilitating neurologic disorder in which mortality ensues within five years of onset.  The progression of HAM/TSP is characterized by an intense proliferation of chronically activated CD8+ cytotoxic T lymphocytes, 90% of which are specific for the HTLV-1 transactivator protein Tax (11-19) peptide. The genesis and effectiveness of this hyper-activated Tax-specific cytotoxic T cell response remains incompletely characterized and it is still unknown whether this response is beneficial or harmful to the overall pathogenic immunologic process of HAM/TSP. Additionally, it is not fully understood why many individuals that become infected with HTLV-1 maintain low proviral loads throughout life and thus never exhibit disease symptoms (defined as asymptomatic carriers).

With respect to HTLV-1 neuropathogenesis, the major immunologic hallmark of HAM/TSP is the spontaneous proliferation of lymphocytes, the levels of which reflect disease severity.  Depletion of dendritic cells from the patients' peripheral blood mononuclear cells abolishes this proliferation while supplementing dendritic cells, but not other types of antigen presenting cells restore proliferation. Furthermore, dendritic cells are infected by HTLV-1 both in vitro and in HAM/TSP patients.  Collectively, these studies strongly suggest that dendritic cells have a critical role during the progression of HAM/TSP; however, the mechanism of dendritic cell activation and the role of activated dendritic cells in the generation of a Tax-specific immune response remain elusive. The hypothesis guiding the proposed investigations is that the presentation of Tax peptide by activated dendritic cells to naïve (inactive) T cells leads to the induction and regulation of the Tax-specific cytotoxic response characteristic of HAM/TSP. Studies are currently being performed to elucidate the characteristic role of dendritic cells in HTLV-1 associated neuropathogenesis, specifically in HAM/TSP, and facilitate the development of novel therapeutic approaches to prevent HTLV-1 infection or treat HTLV-1 associated disease.