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

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 CD69high phenotype, only a small fraction of them produced IFNg 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+IFNg+, CD69+IFNg-, and CD69-IFNg- subsets, and whether the expansion of the total HLADR+CD38+ CD8 T cells or the IFNg producing CD8 T cells differ depending on disease severity remained unclear. This study addresses these knowledge gaps. We find that the CD69+IFNg+ subset uniquely expressed key genes involved in protein translation, cellular metabolism, proliferation and dendritic cell cross talk. Both the CD69+IFNg+ and CD69+IFNg- 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 IFNg+ CD69+ subset. On the other hand, the CD69- IFNg- 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 IFNg 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.