CD8+ T Cell and NK Responses to a Novel Dengue Epitope: A Possible Role for KIR3DL1 in Dengue Pathogenesis: A Dissertation

Abstract

Variation in the sequence of T cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T cell responses during second heterologous infections contributing to pathology following DENV infection. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein, NS126-34. We predicted higher frequencies of NS126-34-specific CD8 + T cells in PBMC from individuals undergoing secondary, rather than primary, DENV infection due to the expansion of memory CD8 T cells. We generated a tetramer against this epitope (B57-NS126-34 TET) and used it to assess the frequencies and phenotype of antigen-specific T cells in samples from a clinical cohort of children with acute DENV infection established in Bangkok, Thailand. High tetramer-positive T cell frequencies during acute infection were seen in only 1 of 9 subjects with secondary infection. B57-NS126-34-specific, other DENV epitope-specific 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-specific CD8 T cells. In vitro stimulation of CD8 T cell lines, generated against three different DENV epitopes, indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides with substantial upregulation of CD71 detected to peptides which also elicited strong functional responses. CD71 may therefore represent a useful marker of antigenspecific T cell activation.