T cell intrinsic IL-1R signaling licenses effector cytokine production by memory CD4 T cells

Abstract

Abstract Innate cytokines are critical drivers of priming and differentiation of naïve CD4 T cells but their role in memory T cell function is largely undefined. We discovered that while TCR and CD28 ligation are primary requirements for memory T cell reactivation, IL-1 acts as a licensing signal to permit effector cytokine production by pre-committed Th1 (IFNg), Th2 (IL-13, IL-4 and IL-5) and Th17 (IL-17A, IL-17F and IL-22) lineage cells. This licensing function of IL-1 is conserved across effector CD4 T cells generated by diverse pathogenic insults and different routes of infections. We found that Il1r−/− CD4 T cells from spleen as well as small intestine can differentiate in vivo into Th1, Th2 and Th17 lineages at the steady state. However, the same CD4 T cells are unable to secrete effector cytokines following TCR ligation. Our data demonstrates that successful lineage commitment does not translate into productive effector function in the absence of IL-1R signaling. Acute abrogation of IL-1R signaling in vivo also resulted in reduced in situ IL-17A production by primed intestinal Th17 cells. Consistently, reactivation of circulating memory CD4 T cells from healthy human donors with autologous DCs in the presence of hIL-1R antagonist (Anakinra) resulted in significantly diminished IL-17A production. Mechanistically, abrogation of IL-1R signaling during reactivation led to rapid decay of T cell cytokine transcripts. Conversely, the presence of recombinant IL-1b during T cell reactivation rescued destabilized cytokine transcripts in a p38 dependent fashion. Together, these results uncover a novel layer of regulation of memory CD4 T cells and establish a broadly conserved role for IL-1 in memory CD4 T cell effector function.