Polyfunctional and IFN-γ monofunctional human CD4+ T cell populations are molecularly distinct

Pathogen-specific polyfunctional T cellresponses have been associated with favorable clinical outcomes, but it is not known whether molecular differences exist between polyfunctional and monofunctional cytokine-producing T cells. Here, we report that polyfunctional CD4+ T cellsinduced during Plasmodium falciparum (P. falciparum) blood-stage infection in humans have a unique transcriptomic profile compared with IFN-γ monofunctional CD4+ T cellsand, thus, are molecularly distinct. The 14- gene signaturerevealed in P. falciparum–reactive polyfunctional T cellsis associated with cytokine signaling and lymphocyte chemotaxis, and systems biologyanalysis identified IL-27 as an upstream regulator of the polyfunctional gene signature. Importantly, the polyfunctional gene signatureis largely conserved in Influenza-reactive polyfunctional CD4+ T cells, suggesting that polyfunctional T cellshave core characteristics independent of pathogen specificity. This study provides the first evidence to our knowledge that consistent molecular differences exist between polyfunctional and monofunctional CD4+ T cells.