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CD8 T cells are important tools for protection against intracellularly replicating pathogens such as viruses. Previous studies showed that a discrete population of HLADR and CD38-expressing CD8 T cells expands massively during the acute febrile phase of human dengue virus infection--but very few of these cells secrete IFNγ upon in vitro stimulation with dengue peptides. To gain a better understanding of what other cytokines/chemokines do these massively expanding HLADR+CD38+ CD8 T cells express, we performed RNA seq of sorted HLADR+CD38+ CD8 T cell subsets after peptide stimulation. A majority of these peptide-stimulated HLADR+CD38+ CD8 T cells were CD69- IFNγ-, nearly a third were CD69+ IFNγ-, whereas very few (<10%) were CD69+ IFNγ+. The CD69- IFNγ- subset was enriched for the expression of key genes implicated in the negative regulation of T cell receptor (TCR) signaling and T-cell exhaustion, attraction of B cells and other lymphocytes, and cytokines related to Tc17/T-reg lineages or those that are implicated in immunosuppression/immunomodulatory and anti-inflammatory activities and angiogenesis. The CD69+ IFNγ- subset showed enriched transcription of key genes implicated in cytotoxic effector functions as well as costimulatory and signaling adaptors implicated in fine balancing of T cell receptor signaling. The CD69+ IFNγ+ subset largely shared the transcriptional profile with the CD69+ IFNγsubset--but with relatively more pronounced expression along with additional genes such as chemokines XCL1/XCL2. Our findings showing distinct functional subsets among these massively expanding CD8 T cells in dengue CD8 T cells warrant further studies to carefully examine the precise role of these T cell subsets in protection against dengue. [ABSTRACT FROM AUTHOR]