Long-lived effector CD8+ T cells are transcriptionally and functionally distinct from effector memory cells

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Abstract In response to an infection or vaccination, antigen-specific CD8+ T cells have the capacity to differentiate into long-lived memory T cells that ultimately confer critical protection against re-infection. The memory CD8+ T cell population is heterogeneous and comprised of circulating effector memory (Tem) and central memory (Tcm) cells as well as non-circulating memory cells or tissue-resident memory cells (Trm). Each memory T cell subset is characterized by distinct phenotypic and functional attributes as well as localization patterns. It has previously been demonstrated that circulating memory subsets can be further subdivided based on effector function or migration patterns. Here, we contribute to the clarification of this heterogeneity by characterizing the gene expression, functional activity and differentiation requirements of long-lived CD127loCD62Llo effector cells (LLE) that can persist at least one year after infection in mice. LLE were found to be phenotypically and functionally distinct from CD127hiCD62Llo Tem and CD127hiCD62LhiTcm subsets. LLE exhibited a unique transcriptional profile, with genes expressed in common with both CD127loKLRG1hi short-lived effector cells and Tem. Further, we refine roles for key fate-specifying transcription factors in controlling the differentiation of LLE versus Tem subsets. These studies further highlight the extent of memory T cell heterogeneity and may inform novel vaccination strategies.