Differential regulation of TH1, TFH, and TCM gene programs by cytokine-mediated events

Abstract

Abstract During the course of an immune response, multiple effector T helper cell types emerge to combat the initial infection, with subsequent emergence of long-term CD4+ T memory cells to ensure that a second exposure to the same pathogen will not cause disease. CD4+ T helper cell populations that are critical for this process include T helper 1 (TH1) and T follicular Helper (TFH) effector cells and long-lasting central memory T (TCM) cells. Previous work has demonstrated a level of flexibility between effector TH1 and TFH-like cell populations, with the respective gene programs regulated by alterations in interleukin 2 (IL-2) signaling. Here, we demonstrate that in response to decreased IL-2 signaling, effector TH1 cells are capable of initiating the expression of both TFH and TCM-like gene programs, including cell surface expression of IL-6Ra and IL-7R. Importantly, exposure of these cells to either IL-6 or IL-7 augments or inhibits the TFH gene program, respectively, suggesting a potential mechanism whereby cytokine availability may influence TFH or TCM cell function. Consistent with this model, we have identified a novel population of IL-6Ra+IL-7R+ cells that emerge at late time points post-infection in an in vivo mouse model of influenza infection. Further research into the temporal and spatial expression of IL-2, IL-6, and IL-7 in the modulation of these cells represents an exciting avenue of research with wide-ranging therapeutic implications.