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Partial agonist effect influences the CTL response to a heterologous dengue virus serotype
1Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester 01655, USA.
Insights
Secondary dengue virus (DV) infection involves cross-reactive memory T cells (CTL). Variant peptides in heterologous DV serotypes can influence CTL responses during secondary DV infections, impacting disease pathogenesis.
Area of Science:
- Immunology
- Virology
- Pathogenesis of Infectious Diseases
Background:
- Dengue hemorrhagic fever pathogenesis is linked to memory T cell responses during secondary dengue virus (DV) infections.
- Cross-reactive T cell responses between different DV serotypes are crucial in secondary infections.
Purpose of the Study:
- To investigate T cell responses to DV serotypes 2 and 3 (D2V and D3V) in an individual with prior D3V infection.
- To model the impact of heterologous DV serotype variants on T cell responses.
Main Methods:
- Studied peripheral blood mononuclear cells (PBMC) from a D3V-seropositive donor.
- Analyzed CD8+ cytotoxic T lymphocyte (CTL) responses to specific DV NS3 protein epitopes (aa 71-79 and 235-243).
- Utilized IFN-gamma enzyme-linked immunospot assay and CTL clone analysis.
Main Results:
- Identified HLA-B62-restricted CTL epitopes recognized by both D3V-specific and cross-reactive CTLs.
- D2V-reactive CTL clones could lyse D2V-infected cells.
- D2V stimulation of PBMC primarily recognized the 235-243 epitope, with the D2V (71-79) peptide acting as a partial agonist.
Conclusions:
- Variant peptide sequences in heterologous DV serotypes can modulate in vivo CTL responses during secondary DV infection.
- Partial agonism of variant peptides may influence T cell activation and subsequent pathogenesis.
- Understanding these interactions is key to understanding dengue hemorrhagic fever development.
Abstract:
Activation of dengue serotype-cross-reactive memory CTL during secondary dengue virus (DV) infection is thought to be important in the pathogenesis of dengue hemorrhagic fever. To model this effect, we studied the CTL responses to DV types 2 (D2V) and 3 (D3V) in PBMC from an individual previously infected with D3V. DV-specific CD8+ CTL from this donor recognized two HLA-B62-restricted epitopes on the NS3 protein, aa 71-79 (SVKKDLISY) and 235-243 (AMKGLPIRY). Both D3V-specific and D2V/D3V-cross-reactive CTL clones were detected for each epitope; all D2V-reactive CTL clones could lyse D2V-infected autologous cells. CTL responses to both epitopes were detected in bulk cultures stimulated with D3V, but PBMC stimulated with D2V recognized only the 235-243 epitope. IFN-gamma enzyme-linked immunospot assay showed that the D2V (71-79) peptide (DVKKDLISY) did not efficiently activate T cells. Analysis of a CTL clone suggests that the D2V (71-79) peptide acts as a partial agonist, able to sensitize target cells for lysis and inducing only minimal proliferation at high concentrations. These results suggest that variant peptide sequences present in the heterologous DV serotype can influence the CTL response in vivo during secondary DV infection.