Differential Functional Avidity of Dengue Virus-Specific T-Cell Clones for Variant Peptides Representing Heterologous and Previously Encountered Serotypes

Abstract

Proinflammatory cytokines secreted by memory CD8؉ and CD4 ؉ T cells are thought to play a direct role in the pathogenesis of dengue virus infection by increasing vascular permeability and thereby inducing the pathophysiologic events associated with dengue hemorrhagic fever and dengue shock syndrome. Severe disease is frequently observed in the setting of secondary infection with heterologous dengue virus serotypes, suggesting a role for cross-reactive memory T cells in the immunopathogenesis of severe disease. We used a large panel of well-characterized dengue virus-specific CD8 ؉ T-cell clones isolated from Pacific Islanders previously infected with dengue virus 1 to examine effector memory function, focusing on a novel dominant HLA-B*5502-restricted NS5 329-337 epitope, and assessed T-cell responses to stimulation with variant peptides representing heterologous serotypes. Variant peptides were differentially recognized by dengue virus 1-specific effector CD8

Identification of conserved and HLA-A*2402-restricted epitopes in Dengue virus serotype 2

“…However, 17 In the past several years, increasing evidences has indicated that DENV-specific CD8 + T cells are 18 likely to play significant roles in controlling and clearing DENV infection. Initially, some research 19 studies have demonstrated that DENV-specific CD8 + T cells display lytic activity against 20 DENV-infected cells (Imrie et al, 2007;Yauch et al, 2009). Subsequently, researchers found that 21 DENV-specific CD8 + T cells play a crucial role in controlling DENV replication and infection by 22 A c c e p t e d M a n u s c r i p t…”

“…Initially, some research 19 studies have demonstrated that DENV-specific CD8 + T cells display lytic activity against 20 DENV-infected cells (Imrie et al, 2007;Yauch et al, 2009). Subsequently, researchers found that 21 DENV-specific CD8 + T cells play a crucial role in controlling DENV replication and infection by 22 A c c e p t e d M a n u s c r i p t…”

“…All of these data confirm that 14 these nine peptides are restricted by the HLA-A*2402 molecule and should be CD8 + T-cell epitopes. 15 In fact, apart from IFN-γ, both TNF-α and IL-6 can be produced by DENV-specific CD8 + T cells 16 (Imrie et al, 2007). Peptide-specific T cells were next analyzed to determine if peptide immunization 17 could induce TNF-α and IL-6 production.…”

Dengue Virus Serotype-2 Impairs Proliferation of Healthy Donors' T Lymphocytes

“…The role of T lymphocytes in this process is controversial since on the one hand there is evidence that activation of T lymphocytes leads to pro-inflammatory cytokine synthesis [20,21,22,23,24,25,26,27] and on the other there is evidence that T-lymphocyte proliferation in dengue patients is impaired [28,29,30,31] and that patients with acute DENV infection are leukopenic [28,29]. Additionally, there are contradictory results as to whether T lymphocytes can be infected or not with DENV [41,42,43].…”

“…In particular, cross-reactive memory T lymphocytes have been associated with changes in the vasculature, leading to vascular leakage [21,22,23], and activation of T lymphocytes during viremia, which is more evident in DHF, is reflected in the overproduction of cytokines [24]. Furthermore, CD4+ and CD8+ T-lymphocyte clones that proliferate in response to DENV antigens in a serotype cross-reactive fashion have been isolated from dengue patients [25,26,27], thus suggesting that dengue serotype cross-reactive T lymphocytes may contribute to dengue pathogenesis.…”