The role of T-lymphocytes in the pathogenesis of dengue haemorrhagic fever

Moran, Christopher Edward (2007). The role of T-lymphocytes in the pathogenesis of dengue haemorrhagic fever. PhD thesis The Open University.



Dengue is one of the most important human diseases transmitted by an arthropod vector and the incidence of dengue virus infection has been increasing steadily throughout the world. Most infections are asymptomatic but a subset of patients experience a potentially fatal shock syndrome characterised by plasma leakage. Generally attributed to the phenomenon of antibody-dependent enhancement, recent observations indicate that T cells may influence the development of this disease and it is this arm of the immune response to dengue this thesis examines.

It starts by describing the production of novel HLA "tetramers" required for the work and then examines the role played by CD8+ cytotoxic T lymphocytes (CTL). This work demonstrates that CTL showing high level cross reactivity between dengue serotypes tend to exhibit high avidity and can be expanded from blood samples taken during the acute phase of secondary dengue infection. These cells produce much higher levels of both type 1 and certain type 2 cytokines than more serotype specific populations. Highly cross-reactive cells cannot be detected in convalescence when populations demonstrating significant serotype specificity dominate.

The next section of the thesis describes the generation and characterisation of dengue specific CD4+ T cell clones, many of which behave in a highly cross-reactive manner producing large amounts of type 1 cytokines and demonstrating perforin-mediated cytolytic activity associated with an increase in the expression of surface CD107. It debates whether a new epitope has been discovered and discusses the nature of CD4 degeneracy, and its contribution to early cross-reactive immune responses which may facilitate priming of other immune system components.

In conclusion this thesis hypothesises that sequential infection with different dengue virus serotypes elicits highly activated, cross-reactive CTL from memory which produce high levels of pro-inflammatory cytokines. Dengue-specific cross-reactive CD4+ T cell populations are also generated from memory and are capable of producing even greater levels of pro-inflammatory cytokines, and perhaps priming other cell populations. These mediators lead to the development of fluid leak and shock. High-avidity CD8+ T cells are subsequently deleted, perhaps as a consequence of activation-induced cell death, and a more beneficial serotype-specific memory CTL pool generated. These observations have significant implications for our understanding of the role of virus-specific CTL in pathogenesis of dengue disease and consequently for the design of a safe, effective vaccine.

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