Transcriptional profiles of functionally distinct HLADR+CD38+ CD8 T cells subsets from acute febrile dengue patients

Abstract

Abstract Previous studies showed that a discrete population of the CD8 T cells with HLADR + CD38 + phenotype expand massively during the acute febrile phase of dengue natural infection. Although about a third of these massively expanding HLADR + CD38 + CD8 T cells were of CD69 high phenotype, only a small fraction of them produced IFNγ upon in vitro peptide stimulation. What other cytokines/ chemokines do these peptides stimulated HLADR + CD38 + CD8 T cells express, what transcriptional profiles distinguish the CD69 + IFNγ + , CD69 + IFNγ - , and CD69 - IFNγ - subsets, and whether the expansion of the total HLADR + CD38 + CD8 T cells or the IFNγ producing CD8 T cells differ depending on disease severity remained unclear. This study addresses these knowledge gaps. We find that the CD69 + IFNγ + subset uniquely expressed key genes involved in protein translation, cellular metabolism, proliferation and dendritic cell cross talk. Both the CD69 + IFNγ + and CD69 + IFNγ - subsets had an antigen responsive gene signature with genes involved in cytotoxic effector functions, regulation of T cell receptor signaling, signaling by MAPK, chemotaxis and T cell trafficking to inflamed tissues with the expression being more robust in the IFNγ + CD69 + subset. On the other hand, the CD69 - IFNγ - subset was biased towards expression of genes that both augment and dampen T cell responses. Lastly, the expansion of total HLADR + CD38 + CD8 T cells and also the IFNγ producing HLADR + CD38 + CD8 T cells was similar in patients with different grades of disease. Taken together, this study provides valuable insights into the inherent diversity of the effector CD8 T cell response during dengue.