Regulatory T-cells in acute dengue viral infection

Although regulatory T-cells (T-regs) have been shown to be expanded in acute dengue, their role in pathogenesis and their relationship to clinical disease severity and extent of viraemia have not been fully evaluated. The frequency of T-regs was assessed in 56 adult patients with acute dengue by determining the proportion of forkhead box protein 3 (FoxP3) expressing CD4(+) CD25(+)T-cells (FoxP3(+) cells). Dengue virus (DENV) viral loads were measured by quantitative real-time polymerase chain reaction (PCR) and DENV-specific T-cell responses were measured by ex-vivo interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assays to overlapping peptide pools of DENV-NS3, NS1 and NS5. CD45RA and CCR4 were used to phenotype different subsets of T-cells and their suppressive potential was assessed by their expression of cytotoxic T lymphocyte-antigen 4 (CTLA-4) and Fas. While the frequency of FoxP3(+) cells in patients was significantly higher (P < 0.0001) when compared to healthy individuals, they did not show any relationship with clinical disease severity or the degree of viraemia. The frequency of FoxP3(+) cells did not correlate with either ex-vivo IFN-gamma DENV-NS3-, NS5- or NS1-specific T-cell responses. FoxP3(+) cells of patients with acute dengue were predominantly CD45RA(+) FoxP3(low), followed by CD45RA-FoxP3(low), with only a small proportion of FoxP3(+) cells being of the highly suppressive effector T-reg subtype. Expression of CCR4 was also low in the majority of T-cells, with only CCR4 only being expressed at high levels in the effector T-reg population. Therefore, although FoxP3(+) cells are expanded in acute dengue, they predominantly consist of naive T-regs, with poor suppressive capacity.