Heterogeneity and dynamics of DENV-specific CD8 + T cells in dengue infection.
Srikor S., Sungnak W., Trakoolsoontorn C., Poonpanichakul T., Jiravejchakul N., Jevapatarakul D., Thungsatianpun N., Opasawatchai A., Dratva L., Kretschmer L., DENFREE Thailand ., Matangkasombut O., Screaton G., Dejnirattisai W., Duangchinda T., Park J., Meyer K., Mongkolsapaya J., Charoensawan V., Teichmann SA., Matangkasombut P.
Dengue virus (DENV) is a major global health threat, with secondary heterotypic infections potentially inducing detrimental memory immune responses. Antigen-specific CD8 + T cells contribute to both protection and pathogenicity, yet how their phenotypic heterogeneity relates to disease severity remains unclear. Here, we performed plate-based single-cell RNA sequencing of circulating DENV-specific CD8 + T cells identified by HLA tetramers loaded with DENV NS3-derived epitopes. Using tetramer binding to peptides corresponding to the currently and serologically inferred dominant previously infecting serotypes, we identify distinct CD8 + T cell subsets associated with disease severity. Asymptomatic dengue is enriched for lower tetramer binding cells with moderate cytotoxic programs, whereas dengue hemorrhagic fever is associated with high tetramer binding CX3CR1 + CD8 + T cells exhibiting enhanced expression of genes related to T cell receptor signaling and cytotoxicity. T cell receptor repertoires are similar among symptomatic cases but displayed temporal dynamics. Overall, DENV NS3-specific CD8 + T cells across disease severity and time are associated with distinct transcriptomic states and T cell receptor features.