Polyfunctional and IFN-<b>γ</b> monofunctional human CD4⁺ T cell populations are molecularly distinct.

Abstract

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 <i>Plasmodium</i><i>falciparum</i> (<i>P</i>. <i>falciparum</i>) 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 <i>P</i>. <i>falciparum</i>-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 <i>Influenza</i>-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.