Cross‐Reactive Memory CD8⁺T Cells Alter the Immune Response to Heterologous Secondary Dengue Virus Infections in Mice in a Sequence‐Specific Manner

Abstract

Dengue virus is the causative agent of dengue fever and the more-severe dengue hemorrhagic fever (DHF). Human studies suggest that the increased risk of DHF during secondary infection is due to immunopathology partially mediated by cross-reactive memory T cells from the primary infection. To model T cell responses to sequential infections, we immunized mice with different sequences of dengue virus serotypes and measured the frequency of peptide-specific T cells after infection. The acute response after heterologous secondary infections was enhanced compared with the acute or memory response after primary infection. Also, the hierarchy of epitope-specific responses was influenced by the specific sequence of infection. Adoptive-transfer experiments showed that memory T cells responded preferentially to the secondary infection. These findings demonstrate that cross-reactive T cells from a primary infection alter the immune response during a heterologous secondary infection.

Environmental influences on antibody-enhanced dengue disease outcomes

“…Indeed an EE has been shown to enhances T-cell activity during viral infections (de Sousa et al 2011) and DENV is associated with increasing frequencies of interferon (IFN)-γ and TNF-α-producing T-cells after primary infection with all DENV serotypes; secondary infection enhances these responses (Beaumier et al 2010). In a previous report, T-cell responses to sequential infections were measured after mice were immunized with different DENV serotypes and the frequency of peptide-specific T-cells after infection was determined (Beaumier et al 2008). After heterologous secondary infection in BALB/c mice the acute response was enhanced compared with the acute response after primary infection (Beaumier et al 2008).…”

“…In a previous report, T-cell responses to sequential infections were measured after mice were immunized with different DENV serotypes and the frequency of peptide-specific T-cells after infection was determined (Beaumier et al 2008). After heterologous secondary infection in BALB/c mice the acute response was enhanced compared with the acute response after primary infection (Beaumier et al 2008). However, the passive administration of anti-DENV antibodies against one DENV serotype followed 24 h later by inoculation of another serotype of DENV was sufficient to enhance DENV infection and disease in AG129 mice.…”

Distinct activation phenotype of a highly conserved novel HLA‐B57‐restricted epitope during dengue virus infection

“…We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS1 [26][27][28][29][30][31][32][33][34] -specific CD8 + T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer-positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection.…”

“…However, high tetramer-positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57-NS1 [26][27][28][29][30][31][32][33][34] -specific and other DENV epitopespecific CD8 + T cells, as well as total CD8 + T cells, expressed an activated phenotype (CD69 + and/or CD38 + ) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8…”

“…15 We identified a highly conserved nine amino acid epitope on the NS1 protein recognized by HLA-B57-restricted T cells. We hypothesized that B57-NS1 [26][27][28][29][30][31][32][33][34] -specific CD8 + T cells would be preferentially expanded during secondary infection because the epitope sequence would be identical to that seen in primary infection. Using peripheral blood mononuclear cells (PBMC) samples from Thai children with primary or secondary DENV infection, 24 we found that frequencies of B57-NS1 [26][27][28][29][30][31][32][33][34] tetramer-positive T cells were elevated during acute infection.…”