Intrinsic IL-2 Production by Effector CD8 T Cells Attenuates IL-2-signalling and Promotes Fate Decisions, Stemness, and Viral Protection

Interleukin-2 (IL-2) plays pivotal roles in directing the differentiation of effector and memory CD8 T cells; nevertheless, the contributions of IL-2 synthesis by CD8 T cells versus sensitivity to IL-2 signals in shaping their developmental fates and protective efficacy is less clear. Here we show that, rather than acting in an autocrine manner, the production of IL-2 by CD8 T cells restricts their ability to receive STAT5-dependent IL-2 signals, and the capacity to manufacture IL-2 delineates constituents of the expanded effector pool that display stem-like features, preferentially survive, more rapidly attain memory traits, and control chronic viral challenges. Despite having distinct properties during the effector phase, IL-2-producing and non-producing CD8 T cells phenotypically coalesce as memory matures to form populations with equal recall abilities. Therefore, the potential to produce IL-2 during the effector but not memory phase is a consequential cellular feature that dictates the protective capabilities of the response. Naïve P14 CD8 T cells from Ifng.Thy1.1 IL-2.GFP knock in double cytokine reporter mice were transferred into naïve allogenically marked recipient mice one day prior to LCMV-Armstrong infection. Splenocytes from three separate mice were harvested on day 9 (effector) and from four mice on days 308-309 (memory) post infection. THY1.1+ GFP+ (IFN-γ+IL-2+) and THY1.1+ GFP- (IFN-γ+ IL-2-) subsets were sorted directly into Trizo-LSl. RNA was then isolated from the sorted fractions using a Direct-Zol RNA isolation kit (Zymo Research, Irvine CA). RNA samples were then submitted to the UAB Helfin Center for Genomic Science (Birmingham, AL) for quality assessment and RNA sequencing.