Regulation Of CD8 T-cell Function By Multiple Negative Immune Checkpoint Molecules During HTLV-1 Infection

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dc.contributor.advisorNdhlovu, Lishomwa C.
dc.contributor.authorClements, Danielle M.
dc.contributor.departmentBiomedical Sciences
dc.date.accessioned2020-07-07T19:03:54Z
dc.date.issued2020
dc.description.abstractHuman T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive and debilitating inflammatory syndrome of the central nervous system, affects 1–5% of HTLV-1-infected individuals. There is no vaccine for HTLV-1, and treatment options are limited. Cytotoxic T lymphocytes (CTL) play an important role in antiviral immunity and previous studies have shown that CTL dysfunction is associated with increased expression of negative checkpoint receptors (NCRs). NCR expression, particularly the expression of multiple co-expressed NCRs, and whether or not they impact CTL activity has not been fully explored in the context of HTLV-1 infection. The purpose of this research was to determine the extent to which multiple NCRs are expressed on CD8 T cells in HTLV-1 infection and whether NCR blockade effectively enhances the functionality of CTLs in HAM/TSP. We hypothesized that patients with HAM/TSP co-express multiple NCRs on CD8 T cells, and that blocking more than one NCR would enhance CTL function to a greater degree than single-blockade strategies. Results from flow-cytometric analyses demonstrated that different individual NCRs are expressed on T cells from HTLV-1-infected asymptomatic carriers (AC) and HAM/TSP patients. Furthermore, CD8 T cells from HAM/TSP patients co-express multiple NCRs at higher frequencies than AC, including programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3). Higher frequencies of dendritic cells expressing ligands for PD-1 and TIGIT were also observed in HAM/TSP patients. Upon NCR blockade, expression of interferon-gamma (IFN-), cluster of differentiation 107a (CD107a), and tumor necrosis factor- (TNF-a) increased in CD8 T cells in response to HTLV-1 virus to a greater extent when blocked with multiple (>3) blocking monoclonal antibodies (against PD-1, TIGIT, TIM-3 and LAG-3) compared to either single or dual combination blockade. Most interestingly, blockade of both single and multiple NCRs resulted in decreased frequency of IL-2+ CD8 T cells in HAM/TSP patients, but not in AC. The observed reduction in IL-2 expression after blockade may indicate that NCR blockade not only enhances anti-HTLV-1 CTL activity but decreases IL-2 production by anti-HTLV-1-specific CD8 T cells, perhaps leading to a reduction in infected CD4 T-cell proliferation. These results advance our understanding of NCR expression in HTLV-1 infection and supports future exploration of blocking multiple NCRs as a novel immunotherapeutic strategy for HAM/TSP.
dc.description.degreePh.D.
dc.embargo.liftdate2022-07-06
dc.identifier.urihttp://hdl.handle.net/10125/68913
dc.languageeng
dc.publisherUniversity of Hawaii at Manoa
dc.subjectTranslation studies
dc.subjectImmunology
dc.titleRegulation Of CD8 T-cell Function By Multiple Negative Immune Checkpoint Molecules During HTLV-1 Infection
dc.typeThesis
dc.type.dcmiText
local.identifier.alturihttp://dissertations.umi.com/hawii:10702

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Ph.D. - Biomedical Sciences (Tropical Medicine)