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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE137717 | GEO | 2022/01/17

REPOSITORIES: GEO

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Project description:During a T cell response, naÃ¯ve CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells (MPECs) further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. Here, we report that the transcription factor FoxO1 plays an integral role in facilitating effector to memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of scenescence and progressive attrition in polyfunctionality, which in turn led to impared recall responses and poor protective immunity. These data suggest that FoxO1 is essential for active maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow Single-cell suspensions from splenocytes of eight samples WT (control) and FoxO1-/- (experimental) LCMV-immune mice were prepared using standard procedures. CD8 T cells were then isoloated using Thy1.2 (CD90.2) (30-H12) microbeads (Miltenyi Biotec). Cells were then stained with anti-CD8, anti-CD44 and Db/NP396 MHC class I tetramer. Activated (CD8+CD44hi), naive (CD8+CD44lo), and virus-specific CD8 T cells were sorted using FACSAria II instrument (BD Biosciences). The purity of the cells was >95%. Total RNA was extracted from the sorted cells by Trizol Reagent. RNA samples were reverse transcribed and Cy3-labeled cDNAs were hyrbidized to Agilent whole Mouse Genome Oligo Microarrays. Fluorscence signals were detected using Agilent's Microarray Scanner system, data was analyzed using the Rosetta Resolver gene expression data analysis system and genes with a fold change < and p-values <0.01 were identified. Microarray data discussed in the paper is focused on virus-specific memory CD8 T cells from samples WT_Tet_2 vs KO_Tet_2.

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

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