Mechanisms of T cell dysfunction during human T cell leukemia virus type 1 infection
File(s)
Author(s)
Maher, Allison
Type
Thesis
Abstract
Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects 10-20 million people worldwide. While most infected people remain asymptomatic carriers (ACs), 2-5% of HTLV-1 carriers develop adult T-cell leukemia, and another 2-5% develop inflammatory diseases including HTLV-1-associated myelopathy (HAM). HAM is an inflammatory disease of the central nervous system (CNS) with no available curative treatments. Individuals with higher HTLV-1 proviral loads (PVLs) are at an increased risk for HAM development. While CD4+ T cells predominate in early CNS lesions, suggesting their involvement in early HAM pathogenesis, and CD8+ T cells predominate in chronic lesions, much remains to be uncovered about the mechanism of HAM pathogenesis and CNS damage. The overall aims of this work were to study mechanisms of T cell dysfunction during HTLV-1 infection to gain insights into T cell responses associated with effective viral control and the mechanisms by which T cells contribute to HAM pathogenesis.
Here, I show that HTLV-1-specific CD4+ and CD8+ T cells from patients with HAM have an enhanced capacity to migrate to the CNS and can induce proinflammatory astrocytes and microglia. Through in-depth phenotypic, functional, and/or transcriptional characterization of HTLV-1-specific CD4+ and CD8+ T cells, I show that HTLV-1-specific T helper (Th) 17 responses are associated with a low PVL, while an unfocused HTLV-1- specific Th1 response, in addition to a strong HTLV-1-specific T cytotoxic 17 response, are associated with HAM. Finally, I show that CD4+CD8+ double-positive T cells are more abundant in patients with HAM, highly HTLV-1-infected, proinflammatory, have an enhanced capacity to migrate to the CNS and induce inflammatory astrocytes. Taken together, this thesis provides a deeper understanding of the contribution of T cells to CNS inflammation and HAM pathogenesis.
Here, I show that HTLV-1-specific CD4+ and CD8+ T cells from patients with HAM have an enhanced capacity to migrate to the CNS and can induce proinflammatory astrocytes and microglia. Through in-depth phenotypic, functional, and/or transcriptional characterization of HTLV-1-specific CD4+ and CD8+ T cells, I show that HTLV-1-specific T helper (Th) 17 responses are associated with a low PVL, while an unfocused HTLV-1- specific Th1 response, in addition to a strong HTLV-1-specific T cytotoxic 17 response, are associated with HAM. Finally, I show that CD4+CD8+ double-positive T cells are more abundant in patients with HAM, highly HTLV-1-infected, proinflammatory, have an enhanced capacity to migrate to the CNS and induce inflammatory astrocytes. Taken together, this thesis provides a deeper understanding of the contribution of T cells to CNS inflammation and HAM pathogenesis.
Version
Open Access
Date Issued
2024-05
Date Awarded
2024-10
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Dominguez-Villar, Margarita
Taylor, Graham
Sponsor
Wellcome Trust
Rosetrees Trust
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)