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

Pathogen-specific polyfunctional T cell responses 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 cells induced during Plasmodium falciparum ( P . falciparum ) blood-stage infection in humans have a unique transcriptomic profile compared with IFN-γ monofunctional CD4 + T cells and, thus, are molecularly distinct. The 14-gene signature revealed in P . falciparum –reactive polyfunctional T cells is associated with cytokine signaling and lymphocyte chemotaxis, and systems biology analysis identified IL-27 as an upstream regulator of the polyfunctional gene signature. Importantly, the polyfunctional gene signature is largely conserved in Influenza -reactive polyfunctional CD4 + T cells, suggesting that polyfunctional T cells have 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.