Differential Targeting of Viral Components by CD4⁺versus CD8⁺T Lymphocytes in Dengue Virus Infection

Abstract

Dengue virus (DENV) is the principal arthropod-borne viral pathogen afflicting human populations. While repertoires of antibodies to DENV have been linked to protection or enhanced infection, the role of T lymphocytes in these processes remains poorly defined. This study provides a comprehensive overview of CD4(+) and CD8(+) T cell epitope reactivities against the DENV 2 proteome in adult patients experiencing secondary DENV infection. Dengue virus-specific T cell responses directed against an overlapping 15mer peptide library spanning the DENV 2 proteome were analyzed ex vivo by enzyme-linked immunosorbent spot assay, and recognition of individual peptides was further characterized in specific T cell lines. Thirty novel T cell epitopes were identified, 9 of which are CD4(+) and 21 are CD8(+) T cell epitopes. We observe that whereas CD8(+) T cell epitopes preferentially target nonstructural proteins (NS3 and NS5), CD4(+) epitopes are skewed toward recognition of viral components that are also targeted by B lymphocytes (envelope, capsid, and NS1). Consistently, a large proportion of dengue virus-specific CD4(+) T cells have phenotypic characteristics of circulating follicular helper T cells (CXCR5 expression and production of interleukin-21 or gamma interferon), suggesting that they are interacting with B cells in vivo. This study shows that during a dengue virus infection, the protein targets of human CD4(+) and CD8(+) T cells are largely distinct, thus highlighting key differences in the immunodominance of DENV proteins for these two cell types. This has important implications for our understanding of how the two arms of the human adaptive immune system are differentially targeted and employed as part of our response to DENV infection.

Hepatitis B virus–specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation

“…T cell lines were incubated overnight at 37°C with pools of HBV peptides (5 μg/ml), where final DMSO concentrations did not exceed 0.5%. IFN-γ ELISPOT assays (Millipore) were performed as described previously (28).…”

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

“…We also demonstrated that maternal antibodies inhibit seroconversion upon PDK53 vaccination in pups born to PDK53-immune dams. However, we hypothesized that vaccination of these pups with PDK53 may still induce T cell-mediated protection, which usually targets the more conserved nonstructural proteins (17,18,38,39). It was indeed reported that the T cell response to vaccination was not impaired by maternal antibodies (29).…”

Polyclonal antibodies against recombinant dengue virus NS3 protein

“…Además, se ha demostrado que la proteína NS3 es una proteína inmunodominante y uno de los blancos más significativos de la reacción de los linfocitos T durante la infección con el DENV (7,8). Todas estas características la han convertido en un blanco terapéutico valioso y, por lo tanto, en un objeto interesante de estudio.…”